Original Research n Vascular
and Interventional Radiology
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Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation: Risk Factors and Clinical Significance1 Tae Wook Kang, MD Hyo Keun Lim, MD Min Woo Lee, MD Young-sun Kim, MD Hyunchul Rhim, MD Won Jae Lee, MD Geum-Youn Gwak, MD Yong Han Paik, MD Ho Yeong Lim, MD Min Ji Kim, PhD
Purpose:
To evaluate the frequency, risk factors, and clinical significance of aggressive intrasegmental recurrence (AIR) found after radiofrequency (RF) ablation for hepatocellular carcinoma (HCC).
Materials and Methods:
Institutional review board approval was obtained for this retrospective study. Between March 2005 and December 2010, 539 patients (414 men, 125 women; mean age, 57.91 years; age range, 30–82 years) underwent ultrasonography-guided percutaneous RF ablation as a firstline treatment for a single HCC classified as Barcelona Clinic Liver Cancer (BCLC) stage 0 or A. AIR of HCC was defined as (a) initial tumor recurrence with diseasefree status at least 6 months after initial RF ablation and (b) the simultaneous development of multiple nodular (at least three) or infiltrative tumor recurrence in the treated segment. Patients were stratified into two groups: those with AIR (n = 20) and those without AIR (n = 519) during follow-up. Risk factors for AIR were assessed with logistic regression analysis, and risk factors for long-term overall survival were assessed with time-dependent Cox proportional hazard models.
Results:
In a median follow-up period of 49 months (range, 6–95 months), AIR was observed in 3.7% of the patients (20 of 539 patients), with the frequency increasing to 15% in the subgroup with periportal HCC (11 of 72 patients). AIRs manifested as either multiple nodular type (n = 14, BCLC stage A or B) or diffusely infiltrative type with tumor thrombus formation (n = 6, BCLC stage C). At multivariate analysis, periportal tumor location and younger patient age were significant risk factors for AIR. The presence of AIR during the follow-up period has a significant effect on the overall survival rate (hazard ratio = 5.72, P = .002).
Conclusion:
The overall frequency of AIR after RF ablation for HCC was low, with periportal location and patient age showing a significant relationship to the development of AIR. The occurrence of AIR had an adverse effect on overall survival rate.
1
From the Department of Radiology and Center for Imaging Science (T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L.), Division of Hepatology, Department of Medicine (G.Y.G., Y.H.P.), Division of Hematology-Oncology, Department of Medicine (H.Y.L.), and Biostatics Unit, Samsung Biomedical Research Institute (M.J.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Irwonro 81, Seoul 135-710, Republic of Korea; and Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul Republic of Korea (H.K.L., W.J.L., Y.H.P., H.Y.L.). Received May 25, 2014; revision requested July 8; revision received September 12; accepted October 6; final version accepted December 10. Supported by Samsung Medical Center (grant GFO1130071). Address correspondence to H.K.L. (e-mail: [email protected]).
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VASCULAR AND INTERVENTIONAL RADIOLOGY: Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after RF Ablation
T
he therapeutic effectiveness and safety of radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) have been clinically established during the past 15 years, and the procedure is now generally accepted as a curative treatment for very early or early stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) treatment strategy (1). Results of a recent nationwide retrospective study showed that the overall and disease-free survival rates for RF ablation of a single HCC measuring 3 cm or smaller were similar to those for surgical resection (2). During surgical resection, it is possible to perform systematic removal of the corresponding hepatic segment fed by portal tributaries, including potential microvascular invasion as well as the tumor itself (3); however, RF ablation is limited to destruction of the tumor, allowing for some ablative margin, and there is no direct way to treat the remaining segment (4). This restriction is a substantial difference between the two treatment methods because intrahepatic recurrences could arise by means of vascular invasion and subsequent transportal spread along intrasegmental branches or untreated micrometastases around the tumor, which are related to poor prognosis after hepatic resection (5–9).
Advances in Knowledge nn The frequency of aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) after radiofrequency (RF) ablation as a first-line treatment in patients with a single very early or early stage HCC (Barcelona Clinic Liver Cancer grade 0 or A) was 3.7% (20 of 539 patients), with the frequency increasing to 15% in the subgroup of patients with periportal HCC (11 of 72 patients).
We recently observed an interesting pattern of delayed aggressive recurrence confined to the peripheral portion of treated segments after RF ablation for HCC. Previous studies with a small population suggested that HCC could disseminate via peritumoral vessels during RF ablation procedures and result in an aggressive pattern of intrahepatic recurrences (10–14). However, the actual frequency, predisposing factors, and clinical significance of this occurrence have not yet been adequately addressed. We performed this study to evaluate the frequency, risk factors, and clinical significance of aggressive intrasegmental recurrence (AIR) of HCC after RF ablation.
Materials and Methods Patients We conducted a retrospective study of our previously collected RF ablation data. The institutional review board of Samsung Medical Center approved our study and waived the requirement to obtain informed consent. However, written informed consent for RF ablation was obtained from all patients before each treatment in accordance with the clinical protocol. Between March 2005 and December 2010, 1682 patients underwent RF ablation for malignant hepatic lesions in the Department of Radiology, Samsung Medical Center. Our institutional inclusion criteria for the treatment of HCC with RF ablation were the same as those in a previous study (15). From these patients, 660 who underwent ultrasonography (US)–guided percutaneous RF ablation as a first-line treatment for a single nodular HCC were enrolled in our study. RF ablation was considered the first-line treatment if the patient had not undergone previous therapy at the
nn At multivariable analysis, periportal tumor location and younger patient age were independent risk factors for AIR after RF ablation. Radiology: Volume 276: Number 1—July 2015 n radiology.rsna.org
Implication for Patient Care nn Considering the high frequency of AIR that developed after RF ablation for periportal HCCs, RF ablation for these tumors should be performed with great caution.
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time of HCC diagnosis. Of the 660 patients who underwent RF ablation, 539 consecutive patients (414 men, 125 women; mean age, 57.91 years; age range, 30–82 years) were selected for our study. Our inclusion criteria were as follows: (a) patients underwent multiphase dynamic computed tomography (CT) before RF ablation; (b) asymptomatic patients had Child-Pugh class A or B cirrhosis (Eastern Cooperative Oncology Group performance status 0, BCLC stage 0 or A); (c) RF ablation was technically successful after the initial treatment; and (d) more than 6 months of follow-up was scheduled. Patients with suboptimal CT images for preprocedural work-up and those who underwent combined treatment with other therapeutic modalities were excluded. RF ablation was considered to be technically successful when the index tumor was completely covered by the ablation zone on immediate follow-up CT images (16). The 539 patients were subdivided into two groups: those with AIR (n = 20) and those without AIR (n = 519) during the follow-up period (Fig 1). In 44 patients, HCC was confirmed with histologic examination of specimens from US-guided percutaneous biopsy before treatment. Published online before print 10.1148/radiol.15141215 Content codes: Radiology 2015; 276:274–285 Abbreviations: AIR = aggressive intrasegmental recurrence BCLC = Barcelona Clinic Liver Cancer CI = confidence interval HCC = hepatocellular carcinoma HR = hazard ratio RF = radiofrequency TACE = transcatheter arterial chemoembolization Author contributions: Guarantors of integrity of entire study, T.W.K., H.K.L.; study concepts/study design or data acquisition or data analysis/ interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, T.W.K., H.K.L., G.Y.G.; clinical studies, T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L., Y.H.P., H.Y.L.; statistical analysis, T.W.K., M.J.K.; and manuscript editing, T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L., G.Y.G., H.Y.L., M.J.K. Conflicts of interest are listed at the end of this article.
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Figure 1
Figure 1: Flow diagram for the study. ECOG = Eastern Cooperative Oncology Group, PEI = percutaneous ethanol injection, RFA = RF ablation, TACE = transcatheter arterial chemoembolization.
In the remaining 495 patients, HCC was diagnosed on the basis of the most current guidelines at the time of RF ablation by using characteristic imaging findings and/or tumor marker analysis (17,18).
AIR of HCC The AIR of HCC was defined as the simultaneous development of multiple nodular (at least three) or infiltrative tumor recurrence in the treated segment of the liver that showed enhancement on hepatic arterial phase images and washout on portal or delayed venous phase images at follow-up. These imaging findings were based on previous studies (10,14,19–21). The AIR was restricted to the initial manifestation of tumor recurrence in patients who were previously considered to have disease-free status at least 6 months after initial RF ablation to avoid confusion with tumor 276
progression from residual tumor and unidentified microscopic metastasis or vascular invasion before treatment. To differentiate AIR from the conventional concept of local tumor progression (16), the site of recurrence was not confined to the margin of the ablation zone. Two radiologists (T.W.K. and H.K.L., with 7 and 28 years of experience in abdominal imaging, respectively), who were blinded to clinical outcomes at the time of data collection, retrospectively reviewed all follow-up images and classified each patient by consensus.
RF Ablation Procedures The terminology used herein to describe RF ablation procedures and therapeutic outcomes is from proposed guidelines from the International Working Group on Image-guided Tumor Ablation (16). All RF ablation procedures were
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performed percutaneously with the patient under moderate sedation and with US guidance by one of five radiologists (M.W.L., W.J.L., H.R., H.K.L., or Y.S.K., with 9, 8, 12, 12, and 8 years of experience with this procedure). The RF ablation procedure was performed as previously described (15). We used commercially available electrode systems with generators (Cool-tip RF System [Covidien, Mansfield, Mass] and VIVA [STARmed, Ilsan, Korea]). A single electrode with a 2- or 3-cm active tip, a cluster electrode (Cool-tip, Covidien), or an adjustable active tip (Proteus RF Electrode, STARmed) was used depending on tumor size, tumor location, and equipment availability. We followed the manufacturer’s recommended protocol and used a multistep incremental increase in power as an algorithm for energy deposition. Our therapeutic objective in RF ablation was to obtain at least 0.5 cm of normal liver surrounding the tumor as an ablative margin, with the exception of subcapsular and perivascular tumors (4,22). When the ablation zone created with a single ablation was not sufficient to cover the index tumor (2 cm) with an adequate ablative margin, a multiple overlapping ablation technique was applied by moving the electrode from one site to another. After the procedure, the electrode path was cauterized to avoid bleeding and tumor seeding during electrode retraction. Contrast material–enhanced multiphase CT scans were obtained immediately after RF ablation to determine the technical success of each treatment and to assess for immediate major complications.
Follow-up Protocol To assess therapeutic outcomes and complications, all patients underwent contrast-enhanced multiphase CT, chest radiography, and laboratory tests, including a-fetoprotein tests, 1 month after initial treatment, every 3 months during the first 2 years, and every 4–6 months thereafter. To characterize and further evaluate indeterminate hepatic lesions seen at follow-up CT, contrastenhanced magnetic resonance (MR) imaging of the liver was performed. If
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extrahepatic recurrence was suspected (on the basis of clinical symptoms or unexplained elevation of a-fetoprotein level), chest CT, brain MR imaging, and whole-body bone scintigraphy were also performed. Modes of recurrence were classified as follows (16): AIR, local tumor progression, intrahepatic distant recurrence, and extrahepatic recurrence. If recurrence was detected during the follow-up period, an individualized plan for second-line treatment was designed on the basis of characteristics of the recurrent tumor and the patient’s liver function and general condition. A multidisciplinary tumor board convened to consider an individualized treatment plan for each patient. Modes of second-line treatment included repeat RF ablation, TACE, sorafenib treatment (available after January 2009 and included under national health coverage after January 2011), radiation therapy, liver transplantation, and conservative management. Treatment responses for these recurrent lesions were based on modified Response Evaluation Criteria in Solid Tumors (23).
Data Analysis We analyzed the frequency and imaging findings of AIR, with a focus on location and pattern of tumor recurrence. For risk factor analysis of AIR, the age, sex, initial a-fetoprotein level, use of antiviral therapy during follow-up, presence of liver cirrhosis, cause of liver disease, Child-Pugh class, performance of biopsy before RF ablation, tumor size, type of electrode used, total ablation time, and number of overlapping ablations for each patient were collected retrospectively from electronic medical records. In addition, tumor margin (well defined, ill defined), enhancement pattern (homogeneous, heterogeneous), and presence of an arterioportal shunt around the index tumor and tumor capsule were also included as possible predictors of microvascular invasion of HCC (24,25). Periportal HCC was defined as an index tumor having any contact with a portal vein greater than or equal to 3 mm on axial images. The optimal threshold for contacting vessel size in our study
was based on that in a previous study (26). The time to all-cause death was defined as the interval between the first RF ablation procedure and either death or the final follow-up visit to the outpatient clinic before March 30, 2013. Data from patients receiving transplanted livers were censored on the day before transplantation.
Statistical Analysis Risk factors for AIR after RF ablation were assessed by using a logistic regression in uni- and multivariate analyses. Possible risk factors with P values of .2 or less at univariate analyses were entered into the final multivariable logistic regression model to examine the significance of each risk factor for AIR after adjusting for other risk factors. Overall survival rates were estimated by using the Kaplan-Meier method in the group with AIR and the group without AIR. To investigate factors that affect overall survival rate, a time-dependent Cox proportional hazards model was used to accommodate the time-dependent covariates such as the occurrence of AIR, local tumor progression, intrahepatic distant recurrence, and extrahepatic recurrence. All statistical analyses were performed by using software (version 9.3; SAS Institute, Cary, NC). P , .05 was indicative of a statistically significant difference. Results Patients Patients were followed up for 6–95 months (mean, 49.44 months; median, 49 months). Among the entire group of 539 patients, 154 were found to have very early stage HCC (BCLC stage 0), whereas the remaining 385 patients had early stage HCC (BCLC stage A) before RF ablation according to the current guidelines (1). Additional demographic and clinical characteristics of the patients are shown in Table 1. AIR of HCC Frequency.—During the entire follow-up period, AIR was observed in
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20 of the 539 patients (3.7%). In the subgroup with periportal HCC, however, the frequency of AIR markedly increased to 15% (11 of 72 patients). The median time after initial RF ablation to development of AIR of HCC was 17.5 months (range, 7–39 months). Fourteen of the 20 patients with AIR (70%) had an elevated a-fetoprotein level at the time of its occurrence. Imaging findings.—The identified AIRs were seen as either multiple nodular tumors (n = 14) or as a diffusely infiltrative mass (n = 6) at follow-up CT and/or MR imaging. The multiple tumor nodules were all relatively uniform in size and developed simultaneously in the same segment of the liver peripheral to the ablation zone (Fig 2). The mean number of nodular HCC recurrences was 5.4 (range, 3–7). Diffusely infiltrative tumor recurrences also developed in the peripheral part of the treated segment around the ablation zone. Unlike multiple nodular recurrences, which showed no association with thrombosis in the adjacent portal vein, all tumors of the diffusely infiltrative type were associated with a thrombus in the segmental portal vein adjacent to the ablation zone (Fig 3). Treatment.—All patients with diffusely infiltrative AIR underwent TACE with external radiation therapy to permit concurrent treatment of the tumor thrombus within the portal vein. One of these patients also received sorafenib therapy. Of the patients with multiple nodular-type recurrence, 12 patients were treated with TACE, one patient was treated with TACE and subsequent segmentectomy, and one patient was treated with segmentectomy. Although complete response was achieved in 14 of the 20 patients (70%) after an initial treatment session for control of AIR, eight of the 14 patients (57%) developed tumor relapse in the treated segment during follow-up. Therapeutic results are summarized in Table 2.
Risk Factors for AIR of HCC Univariate analysis revealed that periportal tumor location (P , .001), index tumor size (P = .034), and age (P = .011) were significant factors in terms 277
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Table 1 Baseline Characteristics of 539 Patients and Univariate Analysis of Risk Factors for AIR after RF Ablation Parameter Age at enrollment (y) Male [female] Presence of liver cirrhosis [absence of cirrhosis] Origin of liver disease [hepatitis C virus]‡ Hepatitis B virus Other None Child-Pugh class B [Child-Pugh class A] a-Fetoprotein level (ng/mL)§ Tumor size (cm) Ill-defined tumor margin [well-defined tumor margin] Heterogeneous tumor enhancement [homogeneous tumor enhancement] Presence of peritumoral arterioportal shunt [absence of peritumoral arterioportal shunt] Presence of tumor capsule [absence of tumor capsule] Type of electrode [single with a 2-cm active tip]‡ Single with a 3-cm active tip Single with an adjustable active tip Cluster Total ablation time (min) No. of overlapping ablations Biopsy before RF ablation [noninvasive diagnosis] Periportal location [nonperiportal] History of antiviral treatment [absence]
Univariate Analysis†
All Patients (n = 539)*
Patients with AIR (n = 20)*
Patients without AIR (n = 519)*
Odds Ratio
57.91 6 9.50 414 (76.8) 445 (82.6)
52.50 6 7.82 13 (65) 17 (85)
58.12 6 9.51 401 (77.3) 428 (82.5)
0.94 (0.89, 0.98) 0.55 (0.21, 1.40) 1.20 (0.35, 4.20)
397 (73.7) 40 (7.4) 26 (4.8) 89 (16.5) 16.80 (5.9–88.75) 2.10 6 0.65 157 (29.1) 193 (35.8)
15 (75) 2 (10) 1 (5) 4 (20) 15 (6.6–148.2) 2.41 6 0.72 7 (35) 8 (40)
382 (73.6) 38 (7.3) 25 (4.8) 85 (16.4) 16.90 (5.9–87.1) 2.09 6 0.64 150 (28.9) 185 (35.6)
1.45 (0.23, 9.03) 1.95 (0.17, 22.35) 1.48 (0.08, 29.22) 1.28 (0.42, 3.91) 1.03 (0.80, 1.32) 1.94 (1.05, 3.59) 1.32 (0.52, 3.39) 1.20 (0.48, 3.00)
.011 .208 .770 .933 .999 .999 .999 .669 .841 .034 .557 .691
P Value
41 (7.6)
3 (15)
38 (7.3)
2.23 (0.63, 7.96)
.215
84 (15.6)
3 (15)
81 (15.6)
0.95 (0.27, 3.33)
313 (60.3) 67 (12.9) 64 (12.3) 14.94 6 6.37 1.62 6 0.94 42 (8.1) 61 (11.8) 317 (61.1)
0.88 (0.18, 4.31) 0.75 (0.08, 6.88) 1.56 (0.24, 10.37) 1.04 (0.98, 1.10) 1.40 (0.95, 2.05) 1.26 (0.28, 5.63) 9.18 (3.66, 23.04) 1.18 (0.46, 3.02)
.942 .779 .999 .999 .999 .176 .086 .760 ,.001 .724
324 (60.1) 69 (12.8) 68 (12.6) 15.02 6 6.47 1.63 6 0.96 44 (8.2) 72 (13.3) 330 (61.2)
11 (55) 2 (10) 4 (20) 16.95 6 8.79 2.0 6 1.38 2 (10) 11 (55) 13 (65)
* Except where indicated, data are numbers of patients, with percentages in parentheses, or means 6 standard deviations. †
Odds ratios and P values are derived from logistic regression analysis for univariate analyses. The reference category in each categoric variable is in the bracket in first column. Numbers in parentheses are 95% CIs.
‡
Bonferroni correction was used for P values owing to multiple comparisons.
§
Log-transformation was used for analysis of a-fetoprotein concentration. The a-fetoprotein concentration is presented as the median, with the interquartile range in parentheses.
of occurrence of AIR of HCC after RF ablation (Table 1). At multivariate analysis, however, periportal location (P , .001; odds ratio, 8.66; 95% confidence interval [CI]: 3.29, 22.7) and age (P = .012; odds ratio, 0.93; 95% CI: 0.88, 0.98) showed significance after adjustment for other variables (Table 3).
Influence on BCLC Classification and Long-term Overall Survival Changes in BCLC classification.— BCLC upstaging occurred in all 20 patients who developed AIR after RF ablation. BCLC classification in six patients with very early stage HCC (BCLC stage 0) advanced to 278
intermediate stage (n = 4, BCLC stage B) or advanced stage (n = 2, BCLC stage C), whereas BCLC staging in 14 patients with early stage HCC (BCLC stage A) advanced to intermediate stage (n = 10, BCLC stage B) or advanced stage (n = 4, BCLC stage C). Overall survival.—Twenty-one patients in the group without AIR who underwent liver transplantation were censored during the follow-up period. None of the patients in the group with AIR underwent liver transplantation. Of the 539 patients enrolled, 79 (14.7%) died. Fifty-five patients died of HCC progression, 20 of complications of liver cirrhosis or hepatic failure, and four of other causes. Death
occurred in five of the 20 patients (25%) in the group with AIR (median, 30 months; range, 20–56 months) and in 74 of the 519 (14.3%) without AIR (median, 36.5 months; range, 6–76 months). The overall survival rates at 3 and 5 years were 83.8% and 67.7%, respectively, in the group with AIR and 92.4% and 82.2% in the group without AIR (Fig 4). At multivariate analysis for overall survival rates, occurrence of AIR (P = .002; hazard ratio [HR], 5.72; 95% CI: 1.88, 17.35), intrahepatic distal recurrence (P , .001; HR, 5.10; 95% CI: 2.54, 10.22), extrahepatic recurrence (P , .001; HR, 14.90; 95% CI: 9.13, 24.33), and hepatitis B virus infection (P = .016; HR, 0.40; 95% CI:
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Figure 2
Figure 2: Multiple nodular form of AIR of HCC after RF ablation. (a) Contrast-enhanced axial CT scan obtained during hepatic arterial phase shows HCC (∗) in segment VI before RF ablation. Note index tumor contacting segmental portal vein (arrow). (b) CT scan obtained during portal venous phase 4 months after RF ablation shows that ablation zone (∗) is free from local tumor progression. Neither intrahepatic distant recurrence nor extrahepatic metastasis was found. (c) CT scan obtained during hepatic arterial phase 7 months after RF ablation shows multiple small arterial enhancing nodules (arrows), with delayed washout at equilibrium phase (not shown). These developed simultaneously in peripheral area of treated segment, fed by previous peritumoral portal vein. (d) Superparamagnetic iron oxide–enhanced multishot T2-weighted MR image shows hyperintense lesions corresponding to recurrent multiple nodular HCCs (arrow). (e) Photograph of gross specimen after segmentectomy displays multiple nodular HCCs (∗) in peripheral portion of segment VI at a distance from previous ablation zone (arrows). Patient died of rapid progression of HCC accompanied by multiorgan metastases 56 months after initial RF ablation. (f) Illustration demonstrates multiple nodular-type AIR (arrows) after RF ablation for HCC. ∗ =previous ablation zone.
0.18, 0.88; with hepatitis C virus infection as the reference category) were risk factors that had a significant effect on overall survival (Tables 4, 5).
Discussion Although the possibility of aggressive recurrence by means of intravascular
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spread after RF ablation for HCC has been previously reported (10–14,19–21), to our knowledge this is the first study to report the frequency, risk factors, and 279
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Figure 3
Figure 3: Diffusely infiltrative form of AIR of HCC with tumor thrombus formation after RF ablation. (a) Gadoxetic acid–enhanced MR image obtained during portal venous phase before RF ablation shows HCC (∗) in bottom portion of segment VIII. HCC was diagnosed with percutaneous liver biopsy before treatment because arterial hypervascularization was equivocal. Index tumor was in broad contact with small peritumoral portal vein (arrow). (b) Contrast-enhanced axial CT scan obtained during portal venous phase 7 months after RF ablation shows neither local tumor progression around involution of ablation zone (∗) nor intrahepatic distant recurrence. Adjacent portal veins appear patent, with no evidence of tumor thrombus (arrows). (c) CT scan obtained during hepatic arterial phase 24 months after RF ablation shows ill-defined enhancing lesion with diffusely infiltrative pattern (white arrows) in peripheral portion of ablation zone (∗). Note enhancing tumor thrombi expanding lumen of peritumoral portal vein (black arrow). This was an initial tumor recurrence after RF ablation. (d) CT scan obtained during equilibrium phase 24 months after RF ablation shows delayed washout in both lesions (arrows). Tumor thrombi extend into right main portal vein (P). Patient underwent TACE and subsequent external radiation therapy. However, only partial response was achieved after initial treatment session. (e) CT scan obtained during equilibrium phase 29 months after RF ablation reveals extensive tumor progression in both hepatic lobes. Note hemoperitoneum (∗) resulting from ruptured tumor. Partial iodized oil uptake is seen in tumor thrombi of right portal vein (arrow). Patient died of spontaneous bacterial peritonitis associated with ruptured HCC 30 months after initial RF ablation. (f) Illustration demonstrates diffusely infiltrative type of AIR (arrows) with tumor thrombus formation (arrowheads) in adjacent portal vein after RF ablation for HCC. ∗ = previous ablation zone.
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Multiple (7)/7 Multiple (4)/24 Multiple (5)/8 Multiple (4)/26 Multiple (4)/23 Multiple (6)/7 Multiple (4)/28 Multiple (4)/24 Multiple (5)/7 Diffuse/39 Diffuse/24 Multiple (6)/16 Diffuse/31 Diffuse/7 Diffuse/10 Diffuse/12 Multiple (4)/22 Multiple (7)/11 Multiple (3)/19 Multiple (7)/7
1/57/M 2/41/F 3/40/M 4/54/M 5/68/F 6/50/F 7/67/M 8/54/M 9/57/M 10/44/M 11/43/F 12/58/M 13/49/M 14/48/M 15/56/M 16/49/M 17/61/M 18/53/F 19/46/F 20/55/F
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
RFA 1 1 1 2 2 0 1 1 1 2 1 2 2 2 2 2 1 2 2 2
TACE 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
SUR 0 0 0 0 0 0 0 0 0 1 1 0 1 1 1 1 0 0 0 0
RT No No No No No No No No No No No No No No No Yes No No No No
ST PR CR CR CR CR CR CR CR CR PR PR CR CR PR CR PR PR CR CR CR
Response after Initial Treatment Session‡ NA No Yes Yes Yes No No Yes Yes NA NA Yes No NA No NA NA Yes No Yes
Relapse after Initial Treatment Session§ No No No No No Yes No No No Yes No No No Yes No No No No No No
ER 0 0 0 2 2 0 0 0 0 1 0 1 1 0 0 0 1 0 0 3
RFA 3 1 6 8 5 2 3 2 9 8 1 8 3 6 2 3 4 5 3 3
TACE 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
SUR 0 0 1 0 1 0 0 0 4 2 1 0 1 1 1 1 1 1 0 0
RT
Treatments for HCC during Follow-up†
No No No No No No No No No Yes No No No Yes No Yes No No No No
ST 20 69 72 83 84 56 95 86 51 59 30 59 55 29 25 45 50 35 20 33
Follow-up Period (mo) Death DF DF NDF NDF Death DF NDF Death NDF Death NDF DF Death NDF DF DF DF DF DF
Final Status||
CR = complete response, PR = partial response.
NA = not available. DF = disease free, NDF = not disease free.
‡
§
||
RFA = RF ablation, ST = sorefenib therapy, SUR = surgery. Data indicate numbers of treatments or whether the treatment was performed.
†
* Numbers in parentheses are numbers of nodules.
Note.—The initial treatment session was defined as any treatment for control of tumor recurrence administered within 3 months after diagnosis. Response after the initial treatment session was based on the modified Response Evaluation Criteria in Solid Tumors. Relapse after the initial treatment session was defined as the appearance of new or recurrent tumors in the treated segment at follow-up imaging in tumors that were previously considered to show complete response. Disease-free final status was defined as the absence of tumor in intra- and extrahepatic areas at imaging and clinical examination at the final visit. ER = extrahepatic recurrence.
Type of HCC/Time to AIR Occurrence (mo)*
Patient No./ Age (y)/Sex
Treatments for AIR during Initial Treatment Session†
Treatment Outcomes in 20 Patients with AIR of HCC
Table 2
VASCULAR AND INTERVENTIONAL RADIOLOGY: Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after RF Ablation Kang et al
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Table 3 Multivariate Risk Factor Analysis for AIR after RF Ablation Variable Age at enrollment Tumor size Total ablation time No. of overlapping ablations Periportal location (vs nonperiportal)
Odds Ratio
P Value
0.93 (0.88, 0.98) 1.75 (0.77, 3.98) 0.95 (0.86, 1.05) 1.58 (0.89, 2.82) 8.66 (3.29, 22.77)
.012 .185 .314 .118 ,.001
Note.—Odds ratios and P values are derived from logistic regression analysis for multivariable analyses. Numbers in parentheses are the 95% CI.
Figure 4
Figure 4: Overall survival curves for patients with and patients without AIR of HCC after RF ablation. Curves were obtained with Kaplan-Meier method.
clinical significance of AIR development in a large cohort with long-term follow-up. After RF ablation as a first-line treatment for patients with a single very early or early stage HCC (BLCL stage 0 or A), we found that the occurrence of AIR was relatively rare (3.7% in all patients). However, it markedly increased to 15% in patients with periportal HCC. AIR usually manifested as delayed recurrence after a median recurrence-free period of 17.5 months. On follow-up imaging studies, AIR of HCC manifested as either multiple 282
nodular tumors of relatively uniform size or as an infiltrative mass accompanied by a tumor thrombus within the portal vein. It is interesting that all AIRs in our study were found in the liver parenchyma peripheral to RF ablation zones. Although reversal of portal flow (hepatofugal direction) can be observed in patients with severe portal hypertension, the unique peripheral location of the observed AIRs could suggest the potential for tumor spread via the portal vein in a hepatopetal direction. In line with this assumption, previous
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studies also reported that an increase in intratumoral pressure due to heating could cause dislodgement and spread of cancer cells around the ablation zone by means of the portal venous system (27,28). Although the exact mechanism of this kind of intravascular tumor spread remains unclear, abnormal communications between the hepatic artery and portal vein in HCC, such as an iatrogenic arterioportal fistula (12) or intratumoral shunt (29), have been suggested as possible pathways of cancer cell spread into peripheral liver during RF ablation. Several risk factors appear to promote AIR of HCC after RF ablation in our cohort of patients. These factors were a periportal tumor location and younger patient age. Previous analyses of risk factors for multiple early recurrences of HCC after surgery (5) or RF ablation (19) focused on early tumor recurrence (within 6 or 12 months after treatment, respectively) and found that tumor size, poorly defined tumor margin, presence of intrahepatic metastasis before treatment, and microscopic portal vein tumor thrombi were predictive of early tumor recurrence. These are factors related to tumor biology, notably the presence of microvascular invasion and histologic tumor grade (24,30). However, we did not find any known tumor-related factors among those investigated, including afetoprotein concentration before treatment, tumor size, margin, capsule, enhancement pattern, and peritumoral arterioportal shunt, to be related to occurrence of AIR (24,25). In addition, controversy remains as to whether age can have an influence on pathologic features of HCC, including vascular invasion (31,32). On the basis of these findings, we suspect that the technical aspects of RF ablation procedures for periportal tumors may be some of the factors that promote tumor spread from the ablation zone into the adjacent portal vein via abnormal arterioportal communications in and around tumors. However, these are just our speculations regarding the mechanism underlying AIR of HCC after RF ablation,
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Table 4 Univariate Analysis of Risk Factors for Effect on Overall Survival Variable
HR
Age at enrollment Male [female] Presence of liver cirrhosis [absence] Cause of liver disease [hepatitis C virus]* Hepatitis B virus Other None Child-Pugh class B [Child-Pugh class A] a-Fetoprotein level Tumor size History of antiviral treatment Occurrence of AIR† Occurrence of local tumor progression† Occurrence of intrahepatic distant recurrence† Occurrence of extrahepatic recurrence†
1.00 (0.98, 1.03) 0.81 (0.49, 1.33) 2.01 (0.93, 4.38) 0.42 (0.22, 0.78) 0.58 (0.19, 1.75) 0.54 (0.15, 2.02) 1.02 (0.56, 1.85) 0.97 (0.86, 1.10) 1.34 (0.99, 1.83) 0.65 (0.42, 1.01) 1.86 (0.75, 4.61) 2.81 (1.75, 4.54) 5.78 (3.25, 10.28) 19.99 (12.74, 31.38)
P Value .891 .395 .077 .012 .003 .702 .798 .954 .658 .062 .056 .183 ,.001 ,.001 ,.001
Note.—The reference category for each categoric variable is in the square brackets in first column. Numbers in parentheses are the 95% CI. * Bonferroni correction was used for P values owing to multiple comparisons. †
Time-dependent Cox proportional hazards model was used owing to time-dependent covariates. Analyses of other variables were used for Cox proportional hazards model.
Table 5 Multivariate Analysis of Risk Factors for Effect on Overall Survival Variable
HR
Presence of liver cirrhosis Cause of liver disease [hepatitis C virus]* Hepatitis B virus Other None Tumor size History of antiviral treatment Occurrence of AIR Occurrence of local tumor progression Occurrence of intrahepatic distant recurrence Occurrence of extrahepatic recurrence
2.09 (0.65, 6.77) 0.40 (0.18, 0.88) 0.60 (0.19, 1.90) 0.36 (0.05, 2.64) 0.98 (0.69, 1.40) 0.83 (0.46, 1.50) 5.72 (1.88, 17.35) 1.63 (0.97, 2.74) 5.10 (2.54, 10.22) 14.90 (9.13, 24.33)
P Value .218 .039 .016 .878 .671 .912 .538 .002 .068 ,.001 ,.001
Note.—Time-dependent Cox proportional hazards model was used for multivariate analysis. Numbers in parentheses are the 95% CI. * Bonferroni correction was used for P values owing to multiple comparisons. The reference category is in the square brackets in first column.
and well-designed prospective studies are needed to validate our hypothesis; we cannot exclude the possibility of the presence of multiple foci of undetectable micrometastases or premalignant lesions in a corresponding segment of the liver before RF ablation. However, the sudden simultaneous progression
of these lesions to multiple recurrent tumors of uniform size or a diffuse infiltrative mass accompanied by a tumor thrombus within only a peripheral portion of the treated segment is difficult to explain in this way. In addition, the specific site of recurrence, appearance after a relatively long recurrence-free
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period (33), risk factors from multivariate analysis, and the considerable disparity of the frequency between the periportal and nonperiportal HCC group (15% [11 of 72 patients] vs 1.9% [nine of 467 patients]) could support our hypothesis that this kind of tumor recurrence probably results from transportal tumor spread rather than the progression of pre-existing, undetectable lesions. In all patients with AIR, the tumor BCLC classification was upstaged to indicate progression of disease. In six of 20 patients (30%), disease progressed to an advanced stage, and salvage treatments included repeat TACE, radiation therapy, sorafenib therapy, or surgical resection. Consistent with the upstaging of the BCLC classification, the occurrence of AIR during follow-up had a significant effect on overall survival at multivariable analysis. Although intrahepatic distant recurrence also was a significantly adverse factor for overall survival, the relatively high frequency of AIR in the periportal HCC group seemed to be a more serious problem than intrahepatic distant recurrence, which usually arises from multistep or de novo carcinogenesis in the setting of preneoplastic cirrhotic liver (34). In clinical practice, there are no available guidelines on the use of RF ablation for the treatment of periportal HCC (1). Until conditions for safe and effective RF ablation are better understood, we recommend that careful consideration be given to the treatment for periportal HCCs, especially in younger patients, in view of the relatively high frequency of AIR of HCC observed in our study and the clinical significance of AIR reported herein. Seeking to prevent or minimize this newly recognized tumor recurrence, we recently modified the RF ablation technique in accordance with studies recommending longer ablation times at lower power (28) and have combined RF ablation treatments with TACE (35) for treating periportal HCC. However, the effectiveness of these techniques should be validated with prospective studies. The limitations of our study include, first, the possibility of selection bias 283
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related to the retrospective design. Second, we could not prove the exact cause of AIR because our study was not a prospective case-control study investigating the possible risk factors of AIR. Third, the use of sorafenib for advanced HCC was not consistently used in the study population because national health coverage for sorafenib started after January 2011. This was also the main reason behind TACE with radiation therapy for control of diffusely infiltrative tumor spread with portal vein invasion in the group with AIR (36). Fourth, there was a possibility of having type I errors owing to the high number of predictors considered relative to the number of cases in our study. Finally, we could not include the degree of histologic differentiation in multivariable analysis because we lacked a sufficient number of biopsy-proved HCCs in the study population. In summary, the overall frequency of AIR of HCC was 3.7% (20 of 539 patients) after RF ablation as a first-line treatment in patients with a single very early or early stage HCC (BCLC stage 0 or A), whereas it markedly increased to 15% (11 of 72 patients) in the subgroup with periportal HCC. AIRs were confined to the peripheral area of the treated segment at follow-up imaging. A periportal HCC location and younger age were found to be significant risk factors for AIR of HCC after RF ablation. The development of AIR leads to less favorable survival outcomes. Disclosures of Conflicts of Interest: T.W.K. disclosed no relevant relationships. H.K.L. disclosed no relevant relationships. M.W.L. disclosed no relevant relationships. Y.S.K. disclosed no relevant relationships. H.R. disclosed no relevant relationships. W.J.L. disclosed no relevant relationships. G.Y.G. disclosed no relevant relationships. Y.H.P. disclosed no relevant relationships. H.Y.L. disclosed no relevant relationships. M.J.K. disclosed no relevant relationships.
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15. Kim YS, Lim HK, Rhim H, et al. Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors. J Hepatol 2013;58(1):89–97.
4. Kim YS, Lee WJ, Rhim H, Lim HK, Choi D, Lee JY. The minimal ablative margin of radiofrequency ablation of hepatocellular carcinoma (.2 and ,5 cm) needed to prevent local tumor progression: 3D quantitative assessment using CT image fusion. AJR Am J Roentgenol 2010;195(3):758–765.
16. Goldberg SN, Charboneau JW, Dodd GD III, et al. Image-guided tumor ablation: proposal for standardization of terms and reporting criteria. Radiology 2003;228(2): 335–345.
5. Park JH, Koh KC, Choi MS, et al. Analysis of risk factors associated with early multinodular recurrences after hepatic resection for hepatocellular carcinoma. Am J Surg 2006; 192(1):29–33. 6. Matsumata T, Kanematsu T, Takenaka K, Yoshida Y, Nishizaki T, Sugimachi K. Patterns of intrahepatic recurrence after curative resection of hepatocellular carcinoma. Hepatology 1989;9(3):457–460. 7. Shi M, Zhang CQ, Zhang YQ, Liang XM, Li JQ. Micrometastases of solitary hepatocellular carcinoma and appropriate resection margin. World J Surg 2004;28(4):376–381. 8. Shi M, Guo RP, Lin XJ, et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann Surg 2007;245(1):36–43. 9. Okano A, Hajiro K, Takakuwa H, et al. Diffuse intrahepatic recurrence after resection of hepatocellular carcinoma. Hepatogastroenterology 2000;47(35):1356–1359. 10. Takada Y, Kurata M, Ohkohchi N. Rapid and aggressive recurrence accompanied by portal tumor thrombus after radiofrequency ablation for hepatocellular carcinoma. Int J Clin Oncol 2003;8(5):332–335. 11. Angonese C, Baldan A, Cillo U, et al. Complications of radiofrequency thermal ablation in hepatocellular carcinoma: what about “explosive” spread? Gut 2006;55(3):435– 436. 12. Nicoli N, Casaril A, Abu Hilal M, et al. A case of rapid intrahepatic dissemination of hepatocellular carcinoma after radiofrequency thermal ablation. Am J Surg 2004;188(2): 165–167. 13. Ruzzenente A, Manzoni GD, Molfetta M, et al. Rapid progression of hepatocellular carcinoma after radiofrequency ablation. World J Gastroenterol 2004;10(8):1137–1140. 14. Portolani N, Tiberio GA, Ronconi M, et al. Aggressive recurrence after radiofrequency
17. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42(5):1208–1236. 18. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35(3):421–430. 19. Lee HY, Rhim H, Lee MW, et al. Early diffuse recurrence of hepatocellular carcinoma after percutaneous radiofrequency ablation: analysis of risk factors. Eur Radiol 2013;23(1):190–197. 20. Kotoh K, Enjoji M, Arimura E, et al. Scattered and rapid intrahepatic recurrences after radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol 2005;11(43): 6828–6832. 21. Shiozawa K, Watanabe M, Takahashi M, Wakui N, Iida K, Sumino Y. Analysis of patients with rapid aggressive tumor progression of hepatocellular carcinoma after percutaneous radiofrequency ablation. Hepatogastroenterology 2009;56(96):1689–1695. 22. Nakazawa T, Kokubu S, Shibuya A, et al. Radiofrequency ablation of hepatocellular carcinoma: correlation between local tumor progression after ablation and ablative margin. AJR Am J Roentgenol 2007;188(2):480–488. 23. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30(1): 52–60. 24. Chou CT, Chen RC, Lee CW, Ko CJ, Wu HK, Chen YL. Prediction of microvascular invasion of hepatocellular carcinoma by preoperative CT imaging. Br J Radiol 2012;85 (1014):778–783. 25. Adachi E, Maeda T, Kajiyama K, et al. Factors correlated with portal venous invasion by hepatocellular carcinoma: univariate and multivariate analyses of 232 resected cases without preoperative treatments. Cancer 1996;77(10):2022–2031.
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26. Lu DS, Raman SS, Limanond P, et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv Radiol 2003;14(10):1267–1274. 27. Mori Y, Tamai H, Shingaki N, et al. Diffuse intrahepatic recurrence after percutaneous radiofrequency ablation for solitary and small hepatocellular carcinoma. Hepatol Int 2009; 3(3):509–515. 28. Kotoh K, Nakamuta M, Morizono S, et al. A multi-step, incremental expansion method for radio frequency ablation: optimization of the procedure to prevent increases in intratumor pressure and to reduce the ablation time. Liver Int 2005;25(3):542–547. 29. Choi BI, Lee KH, Han JK, Lee JM. Hepatic arterioportal shunts: dynamic CT and MR features. Korean J Radiol 2002;3(1):1–15.
30. Pawlik TM, Delman KA, Vauthey JN, et al. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 2005;11(9):1086–1092. 31. Lee CR, Lim JH, Kim SH, et al. A comparative analysis of hepatocellular carcinoma after hepatic resection in young versus elderly patients. J Gastrointest Surg 2012; 16(9):1736–1743. 32. Shimada S, Kamiyama T, Yokoo H, et al. Clinicopathological characteristics and prognostic factors in young patients after hepatectomy for hepatocellular carcinoma. World J Surg Oncol 2013;11:52. 33. Furlan A, Marin D, Agnello F, et al. Hepatocellular carcinoma presenting at contrastenhanced multi-detector-row computed tomography or gadolinium-enhanced mag-
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netic resonance imaging as a small (2 cm), indeterminate nodule: growth rate and optimal interval time for imaging follow-up. J Comput Assist Tomogr 2012;36(1):20–25. 34. Park YN. Update on precursor and early lesions of hepatocellular carcinomas. Arch Pathol Lab Med 2011;135(6):704–715. 35. Takuma Y, Takabatake H, Morimoto Y, et al. Comparison of combined transcatheter arterial chemoembolization and radiofrequency ablation with surgical resection by using propensity score matching in patients with hepatocellular carcinoma within Milan criteria. Radiology 2013;269(3):927–937. 36. Kim JY, Chung SM, Choi BO, Kay CS. Hepatocellular carcinoma with portal vein tumor thrombosis: Improved treatment outcomes with external beam radiation therapy. Hepatol Res 2011;41(9):813–824.
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Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation: Risk Factors and Clinical Significance1 Tae Wook Kang, MD Hyo Keun Lim, MD Min Woo Lee, MD Young-sun Kim, MD Hyunchul Rhim, MD Won Jae Lee, MD Geum-Youn Gwak, MD Yong Han Paik, MD Ho Yeong Lim, MD Min Ji Kim, PhD
Purpose:
To evaluate the frequency, risk factors, and clinical significance of aggressive intrasegmental recurrence (AIR) found after radiofrequency (RF) ablation for hepatocellular carcinoma (HCC).
Materials and Methods:
Institutional review board approval was obtained for this retrospective study. Between March 2005 and December 2010, 539 patients (414 men, 125 women; mean age, 57.91 years; age range, 30–82 years) underwent ultrasonography-guided percutaneous RF ablation as a firstline treatment for a single HCC classified as Barcelona Clinic Liver Cancer (BCLC) stage 0 or A. AIR of HCC was defined as (a) initial tumor recurrence with diseasefree status at least 6 months after initial RF ablation and (b) the simultaneous development of multiple nodular (at least three) or infiltrative tumor recurrence in the treated segment. Patients were stratified into two groups: those with AIR (n = 20) and those without AIR (n = 519) during follow-up. Risk factors for AIR were assessed with logistic regression analysis, and risk factors for long-term overall survival were assessed with time-dependent Cox proportional hazard models.
Results:
In a median follow-up period of 49 months (range, 6–95 months), AIR was observed in 3.7% of the patients (20 of 539 patients), with the frequency increasing to 15% in the subgroup with periportal HCC (11 of 72 patients). AIRs manifested as either multiple nodular type (n = 14, BCLC stage A or B) or diffusely infiltrative type with tumor thrombus formation (n = 6, BCLC stage C). At multivariate analysis, periportal tumor location and younger patient age were significant risk factors for AIR. The presence of AIR during the follow-up period has a significant effect on the overall survival rate (hazard ratio = 5.72, P = .002).
Conclusion:
The overall frequency of AIR after RF ablation for HCC was low, with periportal location and patient age showing a significant relationship to the development of AIR. The occurrence of AIR had an adverse effect on overall survival rate.
1
From the Department of Radiology and Center for Imaging Science (T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L.), Division of Hepatology, Department of Medicine (G.Y.G., Y.H.P.), Division of Hematology-Oncology, Department of Medicine (H.Y.L.), and Biostatics Unit, Samsung Biomedical Research Institute (M.J.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Irwonro 81, Seoul 135-710, Republic of Korea; and Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul Republic of Korea (H.K.L., W.J.L., Y.H.P., H.Y.L.). Received May 25, 2014; revision requested July 8; revision received September 12; accepted October 6; final version accepted December 10. Supported by Samsung Medical Center (grant GFO1130071). Address correspondence to H.K.L. (e-mail: [email protected]).
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T
he therapeutic effectiveness and safety of radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) have been clinically established during the past 15 years, and the procedure is now generally accepted as a curative treatment for very early or early stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) treatment strategy (1). Results of a recent nationwide retrospective study showed that the overall and disease-free survival rates for RF ablation of a single HCC measuring 3 cm or smaller were similar to those for surgical resection (2). During surgical resection, it is possible to perform systematic removal of the corresponding hepatic segment fed by portal tributaries, including potential microvascular invasion as well as the tumor itself (3); however, RF ablation is limited to destruction of the tumor, allowing for some ablative margin, and there is no direct way to treat the remaining segment (4). This restriction is a substantial difference between the two treatment methods because intrahepatic recurrences could arise by means of vascular invasion and subsequent transportal spread along intrasegmental branches or untreated micrometastases around the tumor, which are related to poor prognosis after hepatic resection (5–9).
Advances in Knowledge nn The frequency of aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) after radiofrequency (RF) ablation as a first-line treatment in patients with a single very early or early stage HCC (Barcelona Clinic Liver Cancer grade 0 or A) was 3.7% (20 of 539 patients), with the frequency increasing to 15% in the subgroup of patients with periportal HCC (11 of 72 patients).
We recently observed an interesting pattern of delayed aggressive recurrence confined to the peripheral portion of treated segments after RF ablation for HCC. Previous studies with a small population suggested that HCC could disseminate via peritumoral vessels during RF ablation procedures and result in an aggressive pattern of intrahepatic recurrences (10–14). However, the actual frequency, predisposing factors, and clinical significance of this occurrence have not yet been adequately addressed. We performed this study to evaluate the frequency, risk factors, and clinical significance of aggressive intrasegmental recurrence (AIR) of HCC after RF ablation.
Materials and Methods Patients We conducted a retrospective study of our previously collected RF ablation data. The institutional review board of Samsung Medical Center approved our study and waived the requirement to obtain informed consent. However, written informed consent for RF ablation was obtained from all patients before each treatment in accordance with the clinical protocol. Between March 2005 and December 2010, 1682 patients underwent RF ablation for malignant hepatic lesions in the Department of Radiology, Samsung Medical Center. Our institutional inclusion criteria for the treatment of HCC with RF ablation were the same as those in a previous study (15). From these patients, 660 who underwent ultrasonography (US)–guided percutaneous RF ablation as a first-line treatment for a single nodular HCC were enrolled in our study. RF ablation was considered the first-line treatment if the patient had not undergone previous therapy at the
nn At multivariable analysis, periportal tumor location and younger patient age were independent risk factors for AIR after RF ablation. Radiology: Volume 276: Number 1—July 2015 n radiology.rsna.org
Implication for Patient Care nn Considering the high frequency of AIR that developed after RF ablation for periportal HCCs, RF ablation for these tumors should be performed with great caution.
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time of HCC diagnosis. Of the 660 patients who underwent RF ablation, 539 consecutive patients (414 men, 125 women; mean age, 57.91 years; age range, 30–82 years) were selected for our study. Our inclusion criteria were as follows: (a) patients underwent multiphase dynamic computed tomography (CT) before RF ablation; (b) asymptomatic patients had Child-Pugh class A or B cirrhosis (Eastern Cooperative Oncology Group performance status 0, BCLC stage 0 or A); (c) RF ablation was technically successful after the initial treatment; and (d) more than 6 months of follow-up was scheduled. Patients with suboptimal CT images for preprocedural work-up and those who underwent combined treatment with other therapeutic modalities were excluded. RF ablation was considered to be technically successful when the index tumor was completely covered by the ablation zone on immediate follow-up CT images (16). The 539 patients were subdivided into two groups: those with AIR (n = 20) and those without AIR (n = 519) during the follow-up period (Fig 1). In 44 patients, HCC was confirmed with histologic examination of specimens from US-guided percutaneous biopsy before treatment. Published online before print 10.1148/radiol.15141215 Content codes: Radiology 2015; 276:274–285 Abbreviations: AIR = aggressive intrasegmental recurrence BCLC = Barcelona Clinic Liver Cancer CI = confidence interval HCC = hepatocellular carcinoma HR = hazard ratio RF = radiofrequency TACE = transcatheter arterial chemoembolization Author contributions: Guarantors of integrity of entire study, T.W.K., H.K.L.; study concepts/study design or data acquisition or data analysis/ interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, T.W.K., H.K.L., G.Y.G.; clinical studies, T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L., Y.H.P., H.Y.L.; statistical analysis, T.W.K., M.J.K.; and manuscript editing, T.W.K., H.K.L., M.W.L., Y.S.K., H.R., W.J.L., G.Y.G., H.Y.L., M.J.K. Conflicts of interest are listed at the end of this article.
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Figure 1
Figure 1: Flow diagram for the study. ECOG = Eastern Cooperative Oncology Group, PEI = percutaneous ethanol injection, RFA = RF ablation, TACE = transcatheter arterial chemoembolization.
In the remaining 495 patients, HCC was diagnosed on the basis of the most current guidelines at the time of RF ablation by using characteristic imaging findings and/or tumor marker analysis (17,18).
AIR of HCC The AIR of HCC was defined as the simultaneous development of multiple nodular (at least three) or infiltrative tumor recurrence in the treated segment of the liver that showed enhancement on hepatic arterial phase images and washout on portal or delayed venous phase images at follow-up. These imaging findings were based on previous studies (10,14,19–21). The AIR was restricted to the initial manifestation of tumor recurrence in patients who were previously considered to have disease-free status at least 6 months after initial RF ablation to avoid confusion with tumor 276
progression from residual tumor and unidentified microscopic metastasis or vascular invasion before treatment. To differentiate AIR from the conventional concept of local tumor progression (16), the site of recurrence was not confined to the margin of the ablation zone. Two radiologists (T.W.K. and H.K.L., with 7 and 28 years of experience in abdominal imaging, respectively), who were blinded to clinical outcomes at the time of data collection, retrospectively reviewed all follow-up images and classified each patient by consensus.
RF Ablation Procedures The terminology used herein to describe RF ablation procedures and therapeutic outcomes is from proposed guidelines from the International Working Group on Image-guided Tumor Ablation (16). All RF ablation procedures were
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performed percutaneously with the patient under moderate sedation and with US guidance by one of five radiologists (M.W.L., W.J.L., H.R., H.K.L., or Y.S.K., with 9, 8, 12, 12, and 8 years of experience with this procedure). The RF ablation procedure was performed as previously described (15). We used commercially available electrode systems with generators (Cool-tip RF System [Covidien, Mansfield, Mass] and VIVA [STARmed, Ilsan, Korea]). A single electrode with a 2- or 3-cm active tip, a cluster electrode (Cool-tip, Covidien), or an adjustable active tip (Proteus RF Electrode, STARmed) was used depending on tumor size, tumor location, and equipment availability. We followed the manufacturer’s recommended protocol and used a multistep incremental increase in power as an algorithm for energy deposition. Our therapeutic objective in RF ablation was to obtain at least 0.5 cm of normal liver surrounding the tumor as an ablative margin, with the exception of subcapsular and perivascular tumors (4,22). When the ablation zone created with a single ablation was not sufficient to cover the index tumor (2 cm) with an adequate ablative margin, a multiple overlapping ablation technique was applied by moving the electrode from one site to another. After the procedure, the electrode path was cauterized to avoid bleeding and tumor seeding during electrode retraction. Contrast material–enhanced multiphase CT scans were obtained immediately after RF ablation to determine the technical success of each treatment and to assess for immediate major complications.
Follow-up Protocol To assess therapeutic outcomes and complications, all patients underwent contrast-enhanced multiphase CT, chest radiography, and laboratory tests, including a-fetoprotein tests, 1 month after initial treatment, every 3 months during the first 2 years, and every 4–6 months thereafter. To characterize and further evaluate indeterminate hepatic lesions seen at follow-up CT, contrastenhanced magnetic resonance (MR) imaging of the liver was performed. If
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extrahepatic recurrence was suspected (on the basis of clinical symptoms or unexplained elevation of a-fetoprotein level), chest CT, brain MR imaging, and whole-body bone scintigraphy were also performed. Modes of recurrence were classified as follows (16): AIR, local tumor progression, intrahepatic distant recurrence, and extrahepatic recurrence. If recurrence was detected during the follow-up period, an individualized plan for second-line treatment was designed on the basis of characteristics of the recurrent tumor and the patient’s liver function and general condition. A multidisciplinary tumor board convened to consider an individualized treatment plan for each patient. Modes of second-line treatment included repeat RF ablation, TACE, sorafenib treatment (available after January 2009 and included under national health coverage after January 2011), radiation therapy, liver transplantation, and conservative management. Treatment responses for these recurrent lesions were based on modified Response Evaluation Criteria in Solid Tumors (23).
Data Analysis We analyzed the frequency and imaging findings of AIR, with a focus on location and pattern of tumor recurrence. For risk factor analysis of AIR, the age, sex, initial a-fetoprotein level, use of antiviral therapy during follow-up, presence of liver cirrhosis, cause of liver disease, Child-Pugh class, performance of biopsy before RF ablation, tumor size, type of electrode used, total ablation time, and number of overlapping ablations for each patient were collected retrospectively from electronic medical records. In addition, tumor margin (well defined, ill defined), enhancement pattern (homogeneous, heterogeneous), and presence of an arterioportal shunt around the index tumor and tumor capsule were also included as possible predictors of microvascular invasion of HCC (24,25). Periportal HCC was defined as an index tumor having any contact with a portal vein greater than or equal to 3 mm on axial images. The optimal threshold for contacting vessel size in our study
was based on that in a previous study (26). The time to all-cause death was defined as the interval between the first RF ablation procedure and either death or the final follow-up visit to the outpatient clinic before March 30, 2013. Data from patients receiving transplanted livers were censored on the day before transplantation.
Statistical Analysis Risk factors for AIR after RF ablation were assessed by using a logistic regression in uni- and multivariate analyses. Possible risk factors with P values of .2 or less at univariate analyses were entered into the final multivariable logistic regression model to examine the significance of each risk factor for AIR after adjusting for other risk factors. Overall survival rates were estimated by using the Kaplan-Meier method in the group with AIR and the group without AIR. To investigate factors that affect overall survival rate, a time-dependent Cox proportional hazards model was used to accommodate the time-dependent covariates such as the occurrence of AIR, local tumor progression, intrahepatic distant recurrence, and extrahepatic recurrence. All statistical analyses were performed by using software (version 9.3; SAS Institute, Cary, NC). P , .05 was indicative of a statistically significant difference. Results Patients Patients were followed up for 6–95 months (mean, 49.44 months; median, 49 months). Among the entire group of 539 patients, 154 were found to have very early stage HCC (BCLC stage 0), whereas the remaining 385 patients had early stage HCC (BCLC stage A) before RF ablation according to the current guidelines (1). Additional demographic and clinical characteristics of the patients are shown in Table 1. AIR of HCC Frequency.—During the entire follow-up period, AIR was observed in
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20 of the 539 patients (3.7%). In the subgroup with periportal HCC, however, the frequency of AIR markedly increased to 15% (11 of 72 patients). The median time after initial RF ablation to development of AIR of HCC was 17.5 months (range, 7–39 months). Fourteen of the 20 patients with AIR (70%) had an elevated a-fetoprotein level at the time of its occurrence. Imaging findings.—The identified AIRs were seen as either multiple nodular tumors (n = 14) or as a diffusely infiltrative mass (n = 6) at follow-up CT and/or MR imaging. The multiple tumor nodules were all relatively uniform in size and developed simultaneously in the same segment of the liver peripheral to the ablation zone (Fig 2). The mean number of nodular HCC recurrences was 5.4 (range, 3–7). Diffusely infiltrative tumor recurrences also developed in the peripheral part of the treated segment around the ablation zone. Unlike multiple nodular recurrences, which showed no association with thrombosis in the adjacent portal vein, all tumors of the diffusely infiltrative type were associated with a thrombus in the segmental portal vein adjacent to the ablation zone (Fig 3). Treatment.—All patients with diffusely infiltrative AIR underwent TACE with external radiation therapy to permit concurrent treatment of the tumor thrombus within the portal vein. One of these patients also received sorafenib therapy. Of the patients with multiple nodular-type recurrence, 12 patients were treated with TACE, one patient was treated with TACE and subsequent segmentectomy, and one patient was treated with segmentectomy. Although complete response was achieved in 14 of the 20 patients (70%) after an initial treatment session for control of AIR, eight of the 14 patients (57%) developed tumor relapse in the treated segment during follow-up. Therapeutic results are summarized in Table 2.
Risk Factors for AIR of HCC Univariate analysis revealed that periportal tumor location (P , .001), index tumor size (P = .034), and age (P = .011) were significant factors in terms 277
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Table 1 Baseline Characteristics of 539 Patients and Univariate Analysis of Risk Factors for AIR after RF Ablation Parameter Age at enrollment (y) Male [female] Presence of liver cirrhosis [absence of cirrhosis] Origin of liver disease [hepatitis C virus]‡ Hepatitis B virus Other None Child-Pugh class B [Child-Pugh class A] a-Fetoprotein level (ng/mL)§ Tumor size (cm) Ill-defined tumor margin [well-defined tumor margin] Heterogeneous tumor enhancement [homogeneous tumor enhancement] Presence of peritumoral arterioportal shunt [absence of peritumoral arterioportal shunt] Presence of tumor capsule [absence of tumor capsule] Type of electrode [single with a 2-cm active tip]‡ Single with a 3-cm active tip Single with an adjustable active tip Cluster Total ablation time (min) No. of overlapping ablations Biopsy before RF ablation [noninvasive diagnosis] Periportal location [nonperiportal] History of antiviral treatment [absence]
Univariate Analysis†
All Patients (n = 539)*
Patients with AIR (n = 20)*
Patients without AIR (n = 519)*
Odds Ratio
57.91 6 9.50 414 (76.8) 445 (82.6)
52.50 6 7.82 13 (65) 17 (85)
58.12 6 9.51 401 (77.3) 428 (82.5)
0.94 (0.89, 0.98) 0.55 (0.21, 1.40) 1.20 (0.35, 4.20)
397 (73.7) 40 (7.4) 26 (4.8) 89 (16.5) 16.80 (5.9–88.75) 2.10 6 0.65 157 (29.1) 193 (35.8)
15 (75) 2 (10) 1 (5) 4 (20) 15 (6.6–148.2) 2.41 6 0.72 7 (35) 8 (40)
382 (73.6) 38 (7.3) 25 (4.8) 85 (16.4) 16.90 (5.9–87.1) 2.09 6 0.64 150 (28.9) 185 (35.6)
1.45 (0.23, 9.03) 1.95 (0.17, 22.35) 1.48 (0.08, 29.22) 1.28 (0.42, 3.91) 1.03 (0.80, 1.32) 1.94 (1.05, 3.59) 1.32 (0.52, 3.39) 1.20 (0.48, 3.00)
.011 .208 .770 .933 .999 .999 .999 .669 .841 .034 .557 .691
P Value
41 (7.6)
3 (15)
38 (7.3)
2.23 (0.63, 7.96)
.215
84 (15.6)
3 (15)
81 (15.6)
0.95 (0.27, 3.33)
313 (60.3) 67 (12.9) 64 (12.3) 14.94 6 6.37 1.62 6 0.94 42 (8.1) 61 (11.8) 317 (61.1)
0.88 (0.18, 4.31) 0.75 (0.08, 6.88) 1.56 (0.24, 10.37) 1.04 (0.98, 1.10) 1.40 (0.95, 2.05) 1.26 (0.28, 5.63) 9.18 (3.66, 23.04) 1.18 (0.46, 3.02)
.942 .779 .999 .999 .999 .176 .086 .760 ,.001 .724
324 (60.1) 69 (12.8) 68 (12.6) 15.02 6 6.47 1.63 6 0.96 44 (8.2) 72 (13.3) 330 (61.2)
11 (55) 2 (10) 4 (20) 16.95 6 8.79 2.0 6 1.38 2 (10) 11 (55) 13 (65)
* Except where indicated, data are numbers of patients, with percentages in parentheses, or means 6 standard deviations. †
Odds ratios and P values are derived from logistic regression analysis for univariate analyses. The reference category in each categoric variable is in the bracket in first column. Numbers in parentheses are 95% CIs.
‡
Bonferroni correction was used for P values owing to multiple comparisons.
§
Log-transformation was used for analysis of a-fetoprotein concentration. The a-fetoprotein concentration is presented as the median, with the interquartile range in parentheses.
of occurrence of AIR of HCC after RF ablation (Table 1). At multivariate analysis, however, periportal location (P , .001; odds ratio, 8.66; 95% confidence interval [CI]: 3.29, 22.7) and age (P = .012; odds ratio, 0.93; 95% CI: 0.88, 0.98) showed significance after adjustment for other variables (Table 3).
Influence on BCLC Classification and Long-term Overall Survival Changes in BCLC classification.— BCLC upstaging occurred in all 20 patients who developed AIR after RF ablation. BCLC classification in six patients with very early stage HCC (BCLC stage 0) advanced to 278
intermediate stage (n = 4, BCLC stage B) or advanced stage (n = 2, BCLC stage C), whereas BCLC staging in 14 patients with early stage HCC (BCLC stage A) advanced to intermediate stage (n = 10, BCLC stage B) or advanced stage (n = 4, BCLC stage C). Overall survival.—Twenty-one patients in the group without AIR who underwent liver transplantation were censored during the follow-up period. None of the patients in the group with AIR underwent liver transplantation. Of the 539 patients enrolled, 79 (14.7%) died. Fifty-five patients died of HCC progression, 20 of complications of liver cirrhosis or hepatic failure, and four of other causes. Death
occurred in five of the 20 patients (25%) in the group with AIR (median, 30 months; range, 20–56 months) and in 74 of the 519 (14.3%) without AIR (median, 36.5 months; range, 6–76 months). The overall survival rates at 3 and 5 years were 83.8% and 67.7%, respectively, in the group with AIR and 92.4% and 82.2% in the group without AIR (Fig 4). At multivariate analysis for overall survival rates, occurrence of AIR (P = .002; hazard ratio [HR], 5.72; 95% CI: 1.88, 17.35), intrahepatic distal recurrence (P , .001; HR, 5.10; 95% CI: 2.54, 10.22), extrahepatic recurrence (P , .001; HR, 14.90; 95% CI: 9.13, 24.33), and hepatitis B virus infection (P = .016; HR, 0.40; 95% CI:
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Figure 2
Figure 2: Multiple nodular form of AIR of HCC after RF ablation. (a) Contrast-enhanced axial CT scan obtained during hepatic arterial phase shows HCC (∗) in segment VI before RF ablation. Note index tumor contacting segmental portal vein (arrow). (b) CT scan obtained during portal venous phase 4 months after RF ablation shows that ablation zone (∗) is free from local tumor progression. Neither intrahepatic distant recurrence nor extrahepatic metastasis was found. (c) CT scan obtained during hepatic arterial phase 7 months after RF ablation shows multiple small arterial enhancing nodules (arrows), with delayed washout at equilibrium phase (not shown). These developed simultaneously in peripheral area of treated segment, fed by previous peritumoral portal vein. (d) Superparamagnetic iron oxide–enhanced multishot T2-weighted MR image shows hyperintense lesions corresponding to recurrent multiple nodular HCCs (arrow). (e) Photograph of gross specimen after segmentectomy displays multiple nodular HCCs (∗) in peripheral portion of segment VI at a distance from previous ablation zone (arrows). Patient died of rapid progression of HCC accompanied by multiorgan metastases 56 months after initial RF ablation. (f) Illustration demonstrates multiple nodular-type AIR (arrows) after RF ablation for HCC. ∗ =previous ablation zone.
0.18, 0.88; with hepatitis C virus infection as the reference category) were risk factors that had a significant effect on overall survival (Tables 4, 5).
Discussion Although the possibility of aggressive recurrence by means of intravascular
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spread after RF ablation for HCC has been previously reported (10–14,19–21), to our knowledge this is the first study to report the frequency, risk factors, and 279
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Figure 3
Figure 3: Diffusely infiltrative form of AIR of HCC with tumor thrombus formation after RF ablation. (a) Gadoxetic acid–enhanced MR image obtained during portal venous phase before RF ablation shows HCC (∗) in bottom portion of segment VIII. HCC was diagnosed with percutaneous liver biopsy before treatment because arterial hypervascularization was equivocal. Index tumor was in broad contact with small peritumoral portal vein (arrow). (b) Contrast-enhanced axial CT scan obtained during portal venous phase 7 months after RF ablation shows neither local tumor progression around involution of ablation zone (∗) nor intrahepatic distant recurrence. Adjacent portal veins appear patent, with no evidence of tumor thrombus (arrows). (c) CT scan obtained during hepatic arterial phase 24 months after RF ablation shows ill-defined enhancing lesion with diffusely infiltrative pattern (white arrows) in peripheral portion of ablation zone (∗). Note enhancing tumor thrombi expanding lumen of peritumoral portal vein (black arrow). This was an initial tumor recurrence after RF ablation. (d) CT scan obtained during equilibrium phase 24 months after RF ablation shows delayed washout in both lesions (arrows). Tumor thrombi extend into right main portal vein (P). Patient underwent TACE and subsequent external radiation therapy. However, only partial response was achieved after initial treatment session. (e) CT scan obtained during equilibrium phase 29 months after RF ablation reveals extensive tumor progression in both hepatic lobes. Note hemoperitoneum (∗) resulting from ruptured tumor. Partial iodized oil uptake is seen in tumor thrombi of right portal vein (arrow). Patient died of spontaneous bacterial peritonitis associated with ruptured HCC 30 months after initial RF ablation. (f) Illustration demonstrates diffusely infiltrative type of AIR (arrows) with tumor thrombus formation (arrowheads) in adjacent portal vein after RF ablation for HCC. ∗ = previous ablation zone.
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Multiple (7)/7 Multiple (4)/24 Multiple (5)/8 Multiple (4)/26 Multiple (4)/23 Multiple (6)/7 Multiple (4)/28 Multiple (4)/24 Multiple (5)/7 Diffuse/39 Diffuse/24 Multiple (6)/16 Diffuse/31 Diffuse/7 Diffuse/10 Diffuse/12 Multiple (4)/22 Multiple (7)/11 Multiple (3)/19 Multiple (7)/7
1/57/M 2/41/F 3/40/M 4/54/M 5/68/F 6/50/F 7/67/M 8/54/M 9/57/M 10/44/M 11/43/F 12/58/M 13/49/M 14/48/M 15/56/M 16/49/M 17/61/M 18/53/F 19/46/F 20/55/F
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
RFA 1 1 1 2 2 0 1 1 1 2 1 2 2 2 2 2 1 2 2 2
TACE 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
SUR 0 0 0 0 0 0 0 0 0 1 1 0 1 1 1 1 0 0 0 0
RT No No No No No No No No No No No No No No No Yes No No No No
ST PR CR CR CR CR CR CR CR CR PR PR CR CR PR CR PR PR CR CR CR
Response after Initial Treatment Session‡ NA No Yes Yes Yes No No Yes Yes NA NA Yes No NA No NA NA Yes No Yes
Relapse after Initial Treatment Session§ No No No No No Yes No No No Yes No No No Yes No No No No No No
ER 0 0 0 2 2 0 0 0 0 1 0 1 1 0 0 0 1 0 0 3
RFA 3 1 6 8 5 2 3 2 9 8 1 8 3 6 2 3 4 5 3 3
TACE 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
SUR 0 0 1 0 1 0 0 0 4 2 1 0 1 1 1 1 1 1 0 0
RT
Treatments for HCC during Follow-up†
No No No No No No No No No Yes No No No Yes No Yes No No No No
ST 20 69 72 83 84 56 95 86 51 59 30 59 55 29 25 45 50 35 20 33
Follow-up Period (mo) Death DF DF NDF NDF Death DF NDF Death NDF Death NDF DF Death NDF DF DF DF DF DF
Final Status||
CR = complete response, PR = partial response.
NA = not available. DF = disease free, NDF = not disease free.
‡
§
||
RFA = RF ablation, ST = sorefenib therapy, SUR = surgery. Data indicate numbers of treatments or whether the treatment was performed.
†
* Numbers in parentheses are numbers of nodules.
Note.—The initial treatment session was defined as any treatment for control of tumor recurrence administered within 3 months after diagnosis. Response after the initial treatment session was based on the modified Response Evaluation Criteria in Solid Tumors. Relapse after the initial treatment session was defined as the appearance of new or recurrent tumors in the treated segment at follow-up imaging in tumors that were previously considered to show complete response. Disease-free final status was defined as the absence of tumor in intra- and extrahepatic areas at imaging and clinical examination at the final visit. ER = extrahepatic recurrence.
Type of HCC/Time to AIR Occurrence (mo)*
Patient No./ Age (y)/Sex
Treatments for AIR during Initial Treatment Session†
Treatment Outcomes in 20 Patients with AIR of HCC
Table 2
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Table 3 Multivariate Risk Factor Analysis for AIR after RF Ablation Variable Age at enrollment Tumor size Total ablation time No. of overlapping ablations Periportal location (vs nonperiportal)
Odds Ratio
P Value
0.93 (0.88, 0.98) 1.75 (0.77, 3.98) 0.95 (0.86, 1.05) 1.58 (0.89, 2.82) 8.66 (3.29, 22.77)
.012 .185 .314 .118 ,.001
Note.—Odds ratios and P values are derived from logistic regression analysis for multivariable analyses. Numbers in parentheses are the 95% CI.
Figure 4
Figure 4: Overall survival curves for patients with and patients without AIR of HCC after RF ablation. Curves were obtained with Kaplan-Meier method.
clinical significance of AIR development in a large cohort with long-term follow-up. After RF ablation as a first-line treatment for patients with a single very early or early stage HCC (BLCL stage 0 or A), we found that the occurrence of AIR was relatively rare (3.7% in all patients). However, it markedly increased to 15% in patients with periportal HCC. AIR usually manifested as delayed recurrence after a median recurrence-free period of 17.5 months. On follow-up imaging studies, AIR of HCC manifested as either multiple 282
nodular tumors of relatively uniform size or as an infiltrative mass accompanied by a tumor thrombus within the portal vein. It is interesting that all AIRs in our study were found in the liver parenchyma peripheral to RF ablation zones. Although reversal of portal flow (hepatofugal direction) can be observed in patients with severe portal hypertension, the unique peripheral location of the observed AIRs could suggest the potential for tumor spread via the portal vein in a hepatopetal direction. In line with this assumption, previous
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studies also reported that an increase in intratumoral pressure due to heating could cause dislodgement and spread of cancer cells around the ablation zone by means of the portal venous system (27,28). Although the exact mechanism of this kind of intravascular tumor spread remains unclear, abnormal communications between the hepatic artery and portal vein in HCC, such as an iatrogenic arterioportal fistula (12) or intratumoral shunt (29), have been suggested as possible pathways of cancer cell spread into peripheral liver during RF ablation. Several risk factors appear to promote AIR of HCC after RF ablation in our cohort of patients. These factors were a periportal tumor location and younger patient age. Previous analyses of risk factors for multiple early recurrences of HCC after surgery (5) or RF ablation (19) focused on early tumor recurrence (within 6 or 12 months after treatment, respectively) and found that tumor size, poorly defined tumor margin, presence of intrahepatic metastasis before treatment, and microscopic portal vein tumor thrombi were predictive of early tumor recurrence. These are factors related to tumor biology, notably the presence of microvascular invasion and histologic tumor grade (24,30). However, we did not find any known tumor-related factors among those investigated, including afetoprotein concentration before treatment, tumor size, margin, capsule, enhancement pattern, and peritumoral arterioportal shunt, to be related to occurrence of AIR (24,25). In addition, controversy remains as to whether age can have an influence on pathologic features of HCC, including vascular invasion (31,32). On the basis of these findings, we suspect that the technical aspects of RF ablation procedures for periportal tumors may be some of the factors that promote tumor spread from the ablation zone into the adjacent portal vein via abnormal arterioportal communications in and around tumors. However, these are just our speculations regarding the mechanism underlying AIR of HCC after RF ablation,
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Table 4 Univariate Analysis of Risk Factors for Effect on Overall Survival Variable
HR
Age at enrollment Male [female] Presence of liver cirrhosis [absence] Cause of liver disease [hepatitis C virus]* Hepatitis B virus Other None Child-Pugh class B [Child-Pugh class A] a-Fetoprotein level Tumor size History of antiviral treatment Occurrence of AIR† Occurrence of local tumor progression† Occurrence of intrahepatic distant recurrence† Occurrence of extrahepatic recurrence†
1.00 (0.98, 1.03) 0.81 (0.49, 1.33) 2.01 (0.93, 4.38) 0.42 (0.22, 0.78) 0.58 (0.19, 1.75) 0.54 (0.15, 2.02) 1.02 (0.56, 1.85) 0.97 (0.86, 1.10) 1.34 (0.99, 1.83) 0.65 (0.42, 1.01) 1.86 (0.75, 4.61) 2.81 (1.75, 4.54) 5.78 (3.25, 10.28) 19.99 (12.74, 31.38)
P Value .891 .395 .077 .012 .003 .702 .798 .954 .658 .062 .056 .183 ,.001 ,.001 ,.001
Note.—The reference category for each categoric variable is in the square brackets in first column. Numbers in parentheses are the 95% CI. * Bonferroni correction was used for P values owing to multiple comparisons. †
Time-dependent Cox proportional hazards model was used owing to time-dependent covariates. Analyses of other variables were used for Cox proportional hazards model.
Table 5 Multivariate Analysis of Risk Factors for Effect on Overall Survival Variable
HR
Presence of liver cirrhosis Cause of liver disease [hepatitis C virus]* Hepatitis B virus Other None Tumor size History of antiviral treatment Occurrence of AIR Occurrence of local tumor progression Occurrence of intrahepatic distant recurrence Occurrence of extrahepatic recurrence
2.09 (0.65, 6.77) 0.40 (0.18, 0.88) 0.60 (0.19, 1.90) 0.36 (0.05, 2.64) 0.98 (0.69, 1.40) 0.83 (0.46, 1.50) 5.72 (1.88, 17.35) 1.63 (0.97, 2.74) 5.10 (2.54, 10.22) 14.90 (9.13, 24.33)
P Value .218 .039 .016 .878 .671 .912 .538 .002 .068 ,.001 ,.001
Note.—Time-dependent Cox proportional hazards model was used for multivariate analysis. Numbers in parentheses are the 95% CI. * Bonferroni correction was used for P values owing to multiple comparisons. The reference category is in the square brackets in first column.
and well-designed prospective studies are needed to validate our hypothesis; we cannot exclude the possibility of the presence of multiple foci of undetectable micrometastases or premalignant lesions in a corresponding segment of the liver before RF ablation. However, the sudden simultaneous progression
of these lesions to multiple recurrent tumors of uniform size or a diffuse infiltrative mass accompanied by a tumor thrombus within only a peripheral portion of the treated segment is difficult to explain in this way. In addition, the specific site of recurrence, appearance after a relatively long recurrence-free
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period (33), risk factors from multivariate analysis, and the considerable disparity of the frequency between the periportal and nonperiportal HCC group (15% [11 of 72 patients] vs 1.9% [nine of 467 patients]) could support our hypothesis that this kind of tumor recurrence probably results from transportal tumor spread rather than the progression of pre-existing, undetectable lesions. In all patients with AIR, the tumor BCLC classification was upstaged to indicate progression of disease. In six of 20 patients (30%), disease progressed to an advanced stage, and salvage treatments included repeat TACE, radiation therapy, sorafenib therapy, or surgical resection. Consistent with the upstaging of the BCLC classification, the occurrence of AIR during follow-up had a significant effect on overall survival at multivariable analysis. Although intrahepatic distant recurrence also was a significantly adverse factor for overall survival, the relatively high frequency of AIR in the periportal HCC group seemed to be a more serious problem than intrahepatic distant recurrence, which usually arises from multistep or de novo carcinogenesis in the setting of preneoplastic cirrhotic liver (34). In clinical practice, there are no available guidelines on the use of RF ablation for the treatment of periportal HCC (1). Until conditions for safe and effective RF ablation are better understood, we recommend that careful consideration be given to the treatment for periportal HCCs, especially in younger patients, in view of the relatively high frequency of AIR of HCC observed in our study and the clinical significance of AIR reported herein. Seeking to prevent or minimize this newly recognized tumor recurrence, we recently modified the RF ablation technique in accordance with studies recommending longer ablation times at lower power (28) and have combined RF ablation treatments with TACE (35) for treating periportal HCC. However, the effectiveness of these techniques should be validated with prospective studies. The limitations of our study include, first, the possibility of selection bias 283
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related to the retrospective design. Second, we could not prove the exact cause of AIR because our study was not a prospective case-control study investigating the possible risk factors of AIR. Third, the use of sorafenib for advanced HCC was not consistently used in the study population because national health coverage for sorafenib started after January 2011. This was also the main reason behind TACE with radiation therapy for control of diffusely infiltrative tumor spread with portal vein invasion in the group with AIR (36). Fourth, there was a possibility of having type I errors owing to the high number of predictors considered relative to the number of cases in our study. Finally, we could not include the degree of histologic differentiation in multivariable analysis because we lacked a sufficient number of biopsy-proved HCCs in the study population. In summary, the overall frequency of AIR of HCC was 3.7% (20 of 539 patients) after RF ablation as a first-line treatment in patients with a single very early or early stage HCC (BCLC stage 0 or A), whereas it markedly increased to 15% (11 of 72 patients) in the subgroup with periportal HCC. AIRs were confined to the peripheral area of the treated segment at follow-up imaging. A periportal HCC location and younger age were found to be significant risk factors for AIR of HCC after RF ablation. The development of AIR leads to less favorable survival outcomes. Disclosures of Conflicts of Interest: T.W.K. disclosed no relevant relationships. H.K.L. disclosed no relevant relationships. M.W.L. disclosed no relevant relationships. Y.S.K. disclosed no relevant relationships. H.R. disclosed no relevant relationships. W.J.L. disclosed no relevant relationships. G.Y.G. disclosed no relevant relationships. Y.H.P. disclosed no relevant relationships. H.Y.L. disclosed no relevant relationships. M.J.K. disclosed no relevant relationships.
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