Research ArticleClinical Studies

Predicting Poorly Differentiated Hepatocellular Carcinoma that Meets the Milan Criteria

YUKI KOGA, TORU BEPPU, TATSUNORI MIYATA, YUKI KITANO, AKIRA TSUJI, SHIGEKI NAKAGAWA, KOTA ARIMA, KUNITAKA KURAMOTO, HIROHISA OKABE, KATSUNORI IMAI, HIROMITSU HAYASHI, HIDETOSHI NITTA, YO-ICHI YAMASHITA, AKIRA CHIKAMOTO, TAKATOSHI ISHIKO and HIDEO BABA
Anticancer Research July 2018, 38 (7) 4093-4099; DOI: https://doi.org/10.21873/anticanres.12699

Abstract

Background/Aim: Poorly differentiated hepatocellular carcinoma (HCC) is a malignant phenotype following radiofrequency ablation, but not liver resection. This study aimed to identify prognostic parameters that could predict poorly differentiated HCC. Patients and Methods: Between 2007-2014, 158 HCC patients undergoing liver resection were enrolled that not the Milan criteria. Laboratory data were measured including three tumor markers and inflammatory factors (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and monocyte/lymphocyte ratio. Preoperative parameters to predict poorly differentiated HCC were assessed by multivariate logistic regression analysis. Results: Poorly differentiated HCC was observed in 28 (17.7%) patients. In multivariate analysis, two or three positive tumor markers and high NLR (≥2.33) were independent predictors of poorly differentiated HCC. Recurrence-free and overall survival were comparable despite these significant predictors. Conclusion: The preoperative status of two or three positive tumor markers and high NLR facilitated selecting HCC patients with poorly differentiated disease, which will assist making therapeutic decisions for HCC patients.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide (1, 2). Current treatment options for HCC consist of liver transplantation, liver resection, local ablation therapy, transarterial chemoembolization (TACE), and systemic chemotherapy (3). Liver resection and radiofrequency ablation (RFA) are popular curative modalities for HCC 3 cm or less in diameter with three nodules or less (4, 5). RFA is gradually becoming one of the first-choice modalities for small HCC because of its curability, safety and reduced invasiveness compared to liver resection. However, this remains controversial, as it has generally been accepted that the long-term survival after percutaneous RFA of HCC is comparable to that of surgical resection (6-8). In contrast, relatively high local recurrence rates of HCC were reported following RFA; the 3-year local recurrence rate was high, up to 19-27% (9-12). Recurrence after RFA includes aggressive recurrences that have extremely poor outcomes and are thought to arise from neoplastic seeding or intrahepatic dissemination via the epithelial-mesenchymal transition pathway (13-18).

Compared to well-/moderately-differentiated HCC, poorly-differentiated HCC has been defined as a risk factor for local recurrence (13-16) and poor prognosis (19) after local ablation therapy. In contrast, studies have found equivalent prognoses after liver resection in HCC patients with poorly-differentiated components and well-/moderately-differentiated cells (19, 20). Therefore, it is very important to eliminate highly malignant HCC before making decisions about treatment strategy. Previous studies have demonstrated that diagnostic imaging can be useful for predicting poorly differentiated HCC (21-23). For example, we have reported the utility of contrast-to-noise ratio in T2-weighted magnetic resonance imaging (MRI) (24). Nowadays, the apparent diffusion coefficient (ADC) value from MRI using diffusion-weighted imaging (DWI) has been introduced as a useful tool to predict the histological malignancy of HCC (25, 26). The Wakayama University and our group have both reported that the number of positive tumor markers is also useful for predicting the histological malignancy of HCC (27-30). Tumor markers for HCC include alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γ-carboxy prothrombin (DCP).

Systemic inflammatory status can enhance tumor growth, invasion, differentiation, angiogenesis, and metastasis (31-33) in cancer patients. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and monocyte/lymphocyte ratio (MLR) are generally used as markers of inflammation in peripheral blood. Several reports have demonstrated that high preoperative inflammatory status is associated with frequent recurrence or poor prognosis after various HCC treatments (34-37). Therefore, the aim of this study was to identify predictive markers of poorly differentiated HCC before treatment.

Patients and Methods

Patients. Between January 2007 and December 2014, 158 HCC patients undergoing liver resection as an initial treatment at the Department of Gastroenterological Surgery, Kumamoto University Hospital were enrolled into the Milan criteria (38). All HCC diagnoses were based on histological findings from resected specimens. To diagnose and stage HCC prior to surgery, all patients received the following imaging studies: ultrasonography, dynamic computed tomography (CT), enhanced MRI with gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), and CT angiography. Clinicopathological data were collected prospectively. Maximal tumor diameter, tumor number, degree of vessel invasion, and existence of distant metastasis were determined by preoperative imaging. This study was a retrospective, non-interventional, observational study, approved by the institutional ethics committee of the Kumamoto University Hospital (IRB approval number: 971). All patients provided written informed consent before enrollment in the study, which was performed in accordance with the Helsinki Declaration.

Laboratory examinations. Liver function was evaluated by the Child–Pugh classification, indocyanine retention rate at 15 min (ICG-R15) and 99mTc-galactocyl human serum albumin scintigraphy single-photon emission CT imaging (39, 40). Serum levels of AFP, AFP-L3 and protein induced by vitamin K absence or antagonists-II (PIVKA-II) were measured preoperatively, and the number of positive tumor markers (above standard values) were counted. NLR, PLR, and MLR were calculated as previously described (37). All laboratory data were measured within one week before liver resection. A receiver operating characteristic (ROC) curve analysis was implemented to define suitable cut-offs of continuous variables for poorly differentiated HCC.

Liver resection and histological examination. The indication for liver resection was determined by ICG-R15 values and remnant functional volume (41, 42). Liver resection was performed as previously described, and anatomical hepatic resection was planned if liver function was well preserved (43, 44). Histological examinations included tumor differentiation (well, moderate, or poor) and vessel invasion (hepatic artery, portal vein, hepatic vein, and bile duct), which were evaluated according to the Criteria of the Liver Cancer Study Group of Japan (45). Tumor differentiation in each patient was made on the lowest-grade of differentiation found in the resected specimen. Patients were divided into two groups: poorly-differentiated and well-/moderately-differentiated HCC (20, 28). The degrees of liver inflammation and liver fibrosis were defined as A0 to A3 and F0 to F4, respectively, by the Inuyama classification (46).

Follow-up. Regular follow-up was scheduled on an outpatient basis every 3-4 months with contrast-enhanced CT or EOB-MRI and measuring levels of the three tumor markers. Recurrence was defined as the first appearance of a lesion with radiological features typical of HCC and was confirmed by diagnostic imaging and re-elevating tumor markers. The end of follow-up was the date of last follow-up (December 12, 2016) or date of patient death.

Statistical analysis. Continuous variables are expressed as median (range) or mean±standard deviation, as appropriate. Qualitative variables were compared using chi-squared tests, and quantitative variables were compared using the Wilcoxon tests. Variables in which the p-value for the univariate analysis was <0.1 were enrolled in the multivariate logistic regression analysis model. All statistical analyses were performed using JMP version 11 (SAS Institute, Cary, NC, USA).

Results

Clinicopathological characteristics. The clinicopathological characteristics of all patients are shown in Table I. The median age was 69 years (range=39-84 years). Male patients with nonB-nonC hepatitis and Child-Pugh classification A were dominant among this cohort. The median levels of tumor markers were not extremely high. Cut-off values by ROC analysis for NLR, PLR and MLR were 2.33, 85.5 and 0.27, respectively. Increased neutrophil counts over the normal range and decreased lymphocyte counts under the normal range were observed in 18 (11.4%) and 20 (12.7%) patients, respectively. Tumors positive for two and three tumor markers were observed in 36 (22.8%) and 14 (8.9%) patients, respectively. Solitary tumors were found in 136 (86.1%) patients, and the median tumor diameter was 26 mm. Poorly-differentiated tumors were observed in 28 (17.7%) patients.

Predictive factors for poorly differentiated HCC. In univariate analysis, there were five parameters that possibly predicted poorly-differentiated HCC with p-Values <0.1 (Table II). These parameters included positivity for HBs-Ag or HCV-Ab, high NLR (≥2.33), high MLR (≥0.27), positivity for two or three tumor markers, and positive for microvascular invasion. In multivariate analysis, high NLR and positivity for two or three tumor markers were independent predictors for poorly differentiated HCC; odds ratios: 5.27 and 4.14, respectively (Table II). High NLR can result from high neutrophil and/or low lymphocyte numbers. Next, we investigated the relationship between neutrophil count (high vs. normal to low) or lymphocyte count (high to normal vs. low) and poorly differentiated HCC. By Pearson's verification, high neutrophil count (p=0.045), but not low lymphocyte count (p=0.092), was significantly associated with poorly differentiated HCC.

View this table:
Table I.

Clinicopathological factors of HCC patients (n=158).

Predictive value of the number of positive factors for poorly differentiated HCC. Odds ratios from multivariate logistic regression analysis were similar for the two independent factors; therefore, relationships were next assessed between the number of independent factors and the predictive value for poorly differentiated HCC (Table III). Patients with at least one positive factor showed high specificity (0.708) and negative predictive value (0.885). Patients with two positive factors showed excellent sensitivity (0.778), specificity (0.706), positive likelihood ratio (2.644) and positive predictive value (0.9).

Number of positive predictors and RFS and OS after liver resection. With a median observation time of 35.8 (range=1-73) months, recurrence-free survival (RFS) and overall survival (OS) were not significantly different according to the number of significant predictors (Figure 1). The 1-, 3-, and 5-year RFS rates in the groups with 0, 1, and 2 positive predictors were 84%, 82%, and 82%; 44%, 57%, and 64%; and 32%, 54%, and 64%, respectively. The 1-, 3-, and 5-year OS rates in the groups with 0, 1, and 2 positive predictors were 95%, 97%, and 96%; 88%, 91%, and 82%; and 82%, 82%, and 71%, respectively.

Discussion

The current American guidelines recommend that RFA should not be performed for poorly-differentiated HCC due to the possibility of tumor seeding and/or causing a poor prognosis (47). After RFA, patients with poorly-differentiated HCC had distinctly worse survival outcomes compared with those who had well- to moderately-differentiated HCC (19). In contrast, previous studies have demonstrated similar OS rates after liver resection for HCC in the Milan criteria regardless of the degree of tumor differentiation (19, 20). Recently, anatomic resection was shown to provide better long-term survival than non-anatomic resection for patients with solitary poorly-differentiated HCC smaller than 5.0 cm in diameter (44).

Taking biopsies of HCC before ablation therapy is not recommended because of tumor seeding (13). The heterogeneity of HCC tumors is an additional obstacle to obtaining correct tumor differentiation data by biopsy. In this study, tumor differentiation was diagnosed using resected specimen, not biopsy samples. Finally, two independent factors for predicting poorly differentiated HCC were identified. Most notably, patients that were positive for two or more tumors factors showed an excellent predictive value for poorly differentiated HCC (p<0.0001). From the results of this study, among HCC patients who are suitable for both liver resection and local ablation therapy, we strongly recommend liver resection for those who are double- or triple-positive for tumor markers or have high NLR levels. The number of positive tumor markers and NLR are common parameters that do not require any special testing equipment or diagnostic imaging. Even if the standard value of the tumor markers or blood cell count differ from facility to facility, we can still promptly obtain results.

Figure 1.
Figure 1.

Kaplan–Meier survival curves comparing recurrence-free survival (RFS) and overall survival (OS) according to the number of predictive factors. Red line: No predictive factor (n=57); green line: one predictive factor (n=78); blue line: two predictive factors (n=23).

View this table:
Table II.

Univariate and multivariate analyses of independent factors for predicting poorly-differentiated HCC.

We have previously reported that the percentage of poorly differentiated HCC significantly increased only in the triple-positive tumor marker group (17.0% in negative; 17.6% in single-positive; 13.2% in double-positive and 46.4% in triple-positive) (28). This study included only HCC patients undergoing initial liver resection and found that both double- and triple-positive tumor marker status could similarly estimate poorly-differentiated HCC. Kiriyama et al. (27) showed comparable results for HCCs; Edmondson–Steiner classification grade III or IV disease were frequently observed in double- or triple-positive tumor marker groups. For HCC patients undergoing RFA, double- or triple-positive tumor marker status were independent risk factors not only for frequent local recurrence but also for poor prognosis (29, 30). For definitely unresectable HCC patients with highly malignant status, RFA should be performed in combination with chemoembolization, which can improve survival over RFA alone (48).

View this table:
Table III.

Number of independent factors and predictive values for poorly-differentiated HCC.

We have recently demonstrated that NLR is sequentially elevated from pancreatic intraductal papillary mucinous adenoma to pancreatic intraductal papillary mucinous adenocarcinoma, with the cut-off value of 2.07 (49). It has also been reported that NLR might be a useful marker for the differentiation status of benign and malignant thyroid disorders, and the NLR cut-off value for this was 1.91 (50). Interestingly the NLR cutoff value in these studies was relatively low, similar to the 2.33 determined in this study. In fact, our study demonstrated that long-term survival was similar according to the number of positive predictors, including NLR. In contrast, most NLR cut-off values for predicting long-term outcomes of HCC after various therapies varied within higher levels (3.0-5.0) (34). A meta-analysis of HCC patients clearly demonstrated that high NLR was associated with more aggressive phenotypes, such as the presence of vascular invasion, multiple tumors and high AFP levels (34). In contrast, high NLR was correlated with poor differentiation status in two studies, but the results were not significant (51, 52). To our knowledge, this study is the first to show that NLR before liver resection can predict poorly-differentiated HCC.

It is difficult to explain the mechanism whereby poorly-differentiated HCC is associated with a high NLR in the peripheral blood. In HCC patients, a high NLR is closely associated with a high degree of infiltrating tumor-associated macrophages (TAMs). TAMs accelerate systemic neutrophilia by secreting inflammatory cytokines such as IL-6, IL-8, and IL-17 (34, 35, 53) and promote cancer initiation and malignant progression (54). Furthermore, high-level expression of granulocyte colony-stimulating factor in cancer tissues and macrophage colony-stimulating factor in peri-cancerous tissues also influence peripheral neutrophils (34). Neutrophils are the primary source of circulating vascular endothelial growth factor, which has been established as a major contributor to tumor-related angiogenesis and tumor progression (55). NLR reflects an immune microenvironment that favors tumor vascular invasion and suppresses host immune surveillance (55, 56). Conversely, lymphocytes comprise the adaptive, antitumor immune response, and thus their reduction has been shown to promote HCC progression (57, 58).

This study had some limitations. AFP-L3 is not commonly measured worldwide but is spreading from Japan to Western countries. From the result of this study, we recommend measuring AFP-L3, AFP, and PIVKA-II before making treatment decisions for HCC. Although high NLR is a predictor of poorly-differentiated HCC, the mechanism has not been fully elucidated. Of note, these results are limited by the retrospective nature of this study and the small single-center sample size; future large multicenter, prospective studies will be required to validate these findings.

Conclusion

Patients with tumors that are double- or triple-positive for tumor markers and/or have high NLR are likely to contain poorly differentiated HCC components; therefore, liver resection is advised for such patients rather than RFA.

Acknowledgements

The Authors thank James P. Mahaffey, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Footnotes

  • Conflicts of Interest

    The Authors have no competing interests regarding this study.

  • Received May 13, 2018.
  • Revision received June 6, 2018.
  • Accepted June 7, 2018.

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Predicting Poorly Differentiated Hepatocellular Carcinoma that Meets the Milan Criteria
YUKI KOGA, TORU BEPPU, TATSUNORI MIYATA, YUKI KITANO, AKIRA TSUJI, SHIGEKI NAKAGAWA, KOTA ARIMA, KUNITAKA KURAMOTO, HIROHISA OKABE, KATSUNORI IMAI, HIROMITSU HAYASHI, HIDETOSHI NITTA, YO-ICHI YAMASHITA, AKIRA CHIKAMOTO, TAKATOSHI ISHIKO, HIDEO BABA
Anticancer Research Jul 2018, 38 (7) 4093-4099; DOI: 10.21873/anticanres.12699
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