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. Author manuscript; available in PMC: 2021 Jul 1.
Published in final edited form as: HPB (Oxford). 2019 Nov 13;22(7):1004–1010. doi: 10.1016/j.hpb.2019.10.1531

Tumor grade may be used to select patients with multifocal hepatocellular carcinoma for resection

Samantha M Ruff 1, Luke D Rothermel 2, Laurence P Diggs 1, Michael M Wach 1, Reed I Ayabe 1, Sean P Martin 1, David Boulware 2, Daniel Anaya 2, Jeremy L Davis 1, John E Mullinax 3, Jonathan M Hernandez 1
PMCID: PMC7771330  NIHMSID: NIHMS1653874  PMID: 31734237

Abstract

Background:

While resection is a recommended treatment for patients with stage 1 hepatocellular carcinoma (HCC), it remains controversial for multifocal disease. We sought to identify patients with multifocal HCC with survival after resection similar to patients with clinical stage 1 HCC.

Methods:

The National Cancer Database was queried to identify patients that underwent resection for HCC.

Results:

In this study, 2990 patients with a single tumor, and 1087 patients with multifocal disease confined to one lobe underwent resection. In the multifocal cohort, patients with clinical stage 3 (HR 1.54, CI 1.31–1.81, p < 0.0001) or 4 (HR 2.27, CI 1.57–3.29, p < 0.0001) disease, and those with moderately-differentiated (HR 1.32, CI 1.06–1.64, p = 0.012) or poorly differentiated/undifferentiated tumors (HR 1.53, CI 1.20–1.95, p = 0.0006) were associated with worse overall survival (OS). There was no difference in OS between patients with well-differentiated clinical stage 2 multifocal HCC and those with all grades of clinical stage 1 HCC (median of 84.8 (CI 66.3–107.2) vs 76.2 months (CI 71.2–81.3), respectively, p = 0.356).

Conclusions:

Patients with well-differentiated, clinical stage 2 multifocal HCC confined to one lobe experience similar OS following hepatic resection to patients with clinical stage 1 disease. These findings may impact the management of select patients with multifocal HCC.

Introduction

The incidence of hepatocellular carcinoma (HCC) in the United States has risen steadily over the past 20 years and is projected to continue to do so for the next decade. This is attributed principally to the incidence of hepatitis C and to an increasing number of Americans with nonalcoholic fatty liver disease (NAFLD).1 Cirrhosis is not only the main driver of HCC (85–95% of cases), but also one of the main factors limiting treatment options. For patients suffering from HCC and advanced cirrhosis, liver transplantation is the optimal approach as it treats both the tumor and underlying liver disease. Patients with ostensibly normal hepatic function or limited dysfunction and early HCC are potential candidates for resection. Resection is typically reserved for patients with solitary tumors confined to one lobe and without evidence of vascular invasion. For patients with multifocal HCC, resection is controversial given its association with high rates of recurrence and limited overall survival.2

Multifocal tumors are thought to represent either intrahepatic metastasis or multiple primary tumors suggesting more aggressive biologic behavior.2 Outcomes vary considerably among patients with multifocal HCC. Specifically, there are favorable tumor characteristics that correlate with improved survival. Patients with multifocal disease confined to a single lobe have shown previously to achieve superior overall and recurrence-free survival with resection compared to patients with multilobar disease.3 However, improved survival associated with resection for multifocal disease confined to one lobe (versus multilobar) should not be interpreted as an indication for resection. Although a definitive indication for resection in the management of multifocal HCC would require a randomized trial, we sought to contribute selection criteria by evaluating readily available pre-operative factors associated with optimal survival. We defined optimal survival as overall survival not different to that observed with resection for patients with stage 1 disease.

Methods

Data source

This study used the National Cancer Database (2004–2015) to perform a retrospective review and did not require approval from our institutional review board. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.

Study population

This study identified patients with the histologic diagnosis of hepatocellular carcinoma (excluding the fibrolamellar variant) from 2004 to 2015 (International Classification of Diseases for Oncology, ICD-O-3, 8170/3, 8172/3, 8173/3, 8174/3, 8175/3). Using the CS_extension variable, patients included in this study had either multifocal (350, 390, 400, 420) or single tumor (100) disease confined to one lobe. Using the surgery of primary site code, patients who did not undergo surgery (0), underwent local ablative therapy (10–17, 26, 38, 59), transplant (61, 75), excision of only a bile duct (65), or surgery not otherwise specified or unknown (90, 99) were excluded. The surgery code listed in the NCDB is the most invasive procedure that was performed. Patients undergoing transplantation were excluded. Patients who underwent unspecified surgery were excluded since it was unknown whether they were transplanted. Patients with unknown number of lesions, unknown extension of disease, unknown grade, or tumor(s) in more than one hepatic lobe were excluded.

Study and outcome variables

Demographic as well as tumor specific variables were included in the final analysis, including age, gender, race, Charlson-Deyo score, multifocal versus single site disease, grade, stage, lymph/vascular invasion, and fibrosis score. Patients were grouped by race/ethnicity into four categories: Caucasian, African American, Hispanic, or other. Patients of Asian, Indian, American Indian, and Pacific Islander were included in the “other” category. Grade was divided into three categories: well differentiated (grade 1), moderately differentiated (grade 2), and poorly differentiated or undifferentiated (grade 3/4). In the NCDB, grade for patients with multifocal disease is coded as the highest grade from any of the tumors. Patients’ stage was defined using the NCDB’s Clinical Stage variable based on American Joint Committee on Cancer guidelines (7th edition). For survival analysis, a comparative cohort was established inclusive of stage 1 disease to represent the optimal surgical candidate.4 The NCDB’s fibrosis score is grouped into two categories based on the Ishak score, fibrosis score 0–4 (none to moderate fibrosis) and 5–6 (severe fibrosis or cirrhosis). The primary end point for this study was overall survival.

Statistical analysis

Multivariable backwards selection Cox regression was performed for patients with multifocal HCC confined to one lobe who underwent surgery (sls = 0.05). Variables that were not significant were removed from the model during backwards selection. Patients with unknown data were excluded from the multivariable model. Because more than half of the cohort had unknown fibrosis scores, this variable was not included in the multivariable analysis. Lymph/vascular invasion was not included in the analysis given that this variable is consistently known only with the final pathologic evaluation. The multivariable analysis was performed with a significance level of 0.05. Overall survival on Kaplan Meier analysis was calculated from date of diagnosis. If the date of death was not available, overall survival was censored at date of last contact. Statistical tests were performed using SAS® University Edition version 9.4 (SAS Institute Inc., Cary, NC).

Results

Patient and tumor characteristics

Stage 1 HCC

After applying the selection criteria, a total of 2990 patients underwent resection for clinical stage 1 HCC between 2004 and 2015. The median age at diagnosis was 65 years (range 18–90). Patients were predominantly male (N = 2,064, 69.0%), Caucasian (N = 1,775, 59.4%), and with a Charlson-Deyo comorbidity score of 0 (N = 1,444, 48.3%). The majority of patients had an unknown fibrosis score (N = 2,076, 69.4%). Pathological assessment revealed 28.9% (N = 863) of tumors to be well differentiated, 53.1% (N = 1588) moderately differentiated, and 18% (N = 539) poorly differentiated or undifferentiated (Table 1).

Table 1.

Demographics of patients with single lesion and multifocal hepatocellular carcinoma confined to one lobe who underwent surgical resection

Multifocal Cohort N = 1087 (%)a Single Lesion Cohort N = 2990 (%)a p value
Median Arc (Range) 63 (18–90) 65 (18–90) <0.001
Gender 0.002
 Male 894 (74.0) 2064 (69.0)
 Female 283 (26.0) 926 (31.0)
Race 0.250
 Caucasian 657 (60.4) 1775 (59.4)
 African American 168 (15.4) 424 (14.2)
 Other 161 (14.8) 517 (17.3)
 Hispanic 87 (8.0) 250 (8.4)
 Unknown 14 (1.3) 24 (0.8)
Charlson Deyo Score 0.375
 0 543 (50.0) 1444 (48.3)
 1 338 (31.1) 967 (32.3)
 2 117 (10.8) 363 (12.1)
 3+ 89 (8.2) 216 (7.2)
Fibrosis Score 0.161
 Mild-Moderate Fibrosis 171 (15.7) 554 (18.5)
 Severe Fibrosis - Cirrhosis 134 (12.3) 360 (12.0)
 Unknown 782 (71.9) 2076 (69.4)
Grade <0.001
 Well-differentiated 206 (19.0) 863 (28.9)
 Moderately-differentiated 610 (56.1) 1588 (53.1)
 Poorly-differentiated/undifferentiated 271 (24.9) 539 (18.0)
Stage N/A
 1 - 2990 (100)
 2 521 (47.9) -
 3 524 (48.2) -
 4 42 (3.9)
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a

Rounded to nearest percentage.

Multifocal HCC

After applying the selection criteria, a total of 1087 patients underwent resection for multifocal HCC confined to one lobe between 2004 and 2015. The median age at diagnosis was 63 years old (range 18–90). Patients were predominantly male (N = 894, 74.0%), Caucasian (N = 657, 60.4%), and with a Charlson-Deyo comorbidity score of 0 (N = 543, 50.0%). Patients were grouped into clinical stage 2 (N = 521, 47.9%), stage 3 (N = 524, 48.2%), or stage 4 (N = 42, 3.9%). The majority of patients had an unknown fibrosis score (N = 782, 71.9%). Pathological assessment revealed 19% (N = 206) of tumors to be well differentiated, 56.1% (N = 610) moderately differentiated, and 24.9% (N = 271) poorly differentiated or undifferentiated (Table 1).

Survival analysis

Multivariable backwards selection Cox regression was used to identify factors in patients with multifocal disease who underwent surgery that were predictive of survival. Both clinical stage and grade were found to influence survival. Patients with clinical stage 3 (HR 1.54, CI 1.31–1.81, p < 0.0001) and clinical stage 4 (HR 2.27, CI 1.57–3.29, p < 0.0001) disease experienced worse overall survival when compared to patients with clinical stage 2 disease. Moderately differentiated grade (HR 1.32, CI 1.06–1.64, p = 0.012) and poorly differentiated/undifferentiated grade (HR 1.53, CI 1.20–1.95, p = 0.0006) were found to be independently predictive of worse overall survival when compared to tumors with well differentiated histology (Table 2). Increasing age (HR 1.02, CI 1.01–1.02, p = 0.001) and male gender (HR 1.32, CI 1.10–1.58, p = 0.003) were also predictive of worse survival.

Table 2.

Multivariate Backwards Selection Cox Regression for patients with multifocal hepatocellular carcinoma confined to one lobe (N = l,087)

Hazard Ratio Confidence Intervals p value
Age 1.02 1.01–1.02 0.001
Gender
 Female Reference Reference Reference
 Male 1.32 1.10–1.58 0.003
Race
 Caucasian Reference Reference Reference
 African American 1.23 0.99–1.52 0.064
 Other 0.79 0.62–1.00 0.054
 Hispanic 0.89 0.66–1.20 0.456
Grade
 1 (well-differentiated) Reference Reference Reference
 2 (moderately differentiated) 1.32 1.06–1.64 0.012
 3/4 (poorly differentiated, undifferentiated) 1.53 1.20–1.95 0.0006
Stage
 2 Reference Reference Reference
 3 1.54 1.31–1.81 <0.0001
 4 2.27 1.57–3.29 <0.0001
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*

Patients with missing variables were excluded from this analysis.

Charlson- Deyo Score failed to stay significant in this model and is not displayed.

Kaplan–Meier analysis was used to compare subsets of patients with multifocal HCC confined to one lobe to those with clinical stage 1 HCC confined to one lobe. There was a statistically significant difference in survival between patients with clinical stage 2 (all grades) multifocal HCC who underwent surgery and patients with a clinical stage 1 HCC (median overall survival 51.8 months (CI 41.4–61.2) versus 76.2 months (CI 71.2–81.3), respectively, p < 0.0001, Fig. 1A). In addition, there was a statistically significant difference between patients with well differentiated (clinical stages 2–4) multifocal HCC and patients with a clinical stage 1 HCC (median survival 54.7 months (CI 40.7–70.3) versus 76.2 months (CI 71.2–81.3), respectively, p = 0.0005, Fig. 1B). However, there was no statistically significant difference noted when comparing overall survival between patients with well differentiated, clinical stage 2 multifocal HCC confined to one lobe and patients with clinical stage 1 HCC (p = 0.356, Fig. 1C). Median survival was 84.8 months (CI 66.3–107.2) in the well differentiated, clinical stage 2 multifocal cohort and 76.2 months (CI 71.2–81.3) in the clinical stage 1 HCC cohort.

Figure 1.

Figure 1

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Kaplan–Meier survial curve comparing patients who a) underwent surgery with stage 1 versus stage 2 (multifocal only, all grades) HCC b) underwent surgery with stage 1 versus stage 2–4 (multifocal only, well differentiated) HCC c) underwent surgery with stage 1 versus stage 2 (multifocal only, well differentiated) HCC

Discussion

Liver transplantation is the most definitive treatment for HCC, however, the current availability of donor organs often fails to meet demand. As a result, patients with preserved liver function and early-stage disease may undergo primary resection as recommended by current guidelines.5,6 Though resection is traditionally reserved for patients with early stage cancers, recent studies suggest that surgery may benefit a subset of patients with multifocal disease.6–8 We sought to identify the specific subset of patients with multifocal HCC for whom resection could offer similar survival as that of patients with stage 1 HCC, and thereby better delineate a role for resection in this patient population either as potentially curative or as a bridge to transplantation. A large national database was examined to identify equivalent survival for patients with stage I HCC and patients with stage 2 well-differentiated multifocal HCC confined to one lobe. Patients with stage 1 HCC have long been considered optimal surgical candidates. Given the similar outcomes observed in this study, resection may be considered a viable option in the management of well-differentiated stage 2, multifocal HCC.4,9–11

A significant challenge faced by liver transplant candidates relates to long wait-list times associated with limited organ availability. Due to disease progression, many patients lose their transplant eligibility while on waiting lists.12 As such, patients commonly undergo regional treatments as a bridge to transplantation. Most bridging therapies involve loco-regional treatments such as trans-arterial chemoembolization (TACE), radiofrequency ablation (RFA), and microwave ablation (MWA), although these are unlikely to be curative particularly for larger lesions or lesions in difficult anatomic locations.13 Resection is recommended for patients with a single HCC lesion and is considered ideal for small, single site tumors without vascular invasion or impaired liver function due to an associated five-year survival of approximately 60%.11 Importantly, resection can serve as definitive treatment for a large subset of these patients who do not recur.11 We acknowledge that multifocal disease presents an important risk factor for recurrence following resection, although stage and grade can be used to select patients who stand to maximally benefit from the operation.14,15 In Faber et al., tumor grade was found to be a predictor of poor survival in patients with HCC who underwent resection with curative intent.14 Martins-Filho et al. performed a systemic review of tumor grade in HCC and its relationship to prognosis. Overall, they found that most articles showed a correlation between poorly differentiated tumors and worse overall survival and/or disease-free survival.16 In this study, on multivariable analysis, patients with moderately differentiated and poorly differentiated HCC had a higher risk of mortality than those with well differentiated HCC. Perhaps, resection and its associated risk may be acceptable for patients with stage 2 well-differentiated HCC while TACE/MWA may be more appropriate for patients with stage 3, moderately-differentiated, or poorly-differentiated cancers.

Risk of recurrence, particularly recurrence not amenable to further bridging or definitive treatment, is the principle concern when weighing treatment options for multifocal HCC. The etiology of multifocal HCC is either multiple primary tumors or intrahepatic metastases arising from a single HCC primary, both of which are associated with a higher risk of recurrence.17 In addition, for patients with hepatitis-associated HCC, active viremia, multifocal disease, and higher grade have been associated with higher risk of recurrence following surgery.18,19 Among those at highest risk are individuals with chronic hepatitis B and C infections. These viruses are highly oncogenic in nature as they possess the ability to trigger changes in gene expression.20 Active chronic hepatitis infections result in persistent inflammation-induced liver damage and subsequent cirrhosis. Therefore, despite complete tumor extirpation, such patients remain at high risk for recurrence. In recent years, the introduction of nucleoside/nucleotide analogs for hepatitis B and direct-acting antivirals (DAA) for hepatitis C have transformed the management and outcomes of patients with hepatitis.21 A large cohort study of 22,500 patients with Hepatitis C demonstrated that patients who achieved sustained virologic response after DAA, had a decreased risk of HCC.22 Another study following 1,951 patients with Hepatitis B treated with nucleoside/nucleotide analogs for 10 years reported a lower rate of HCC development.23 Although the NCDB does not contain information regarding hepatitis viral status, it is likely that a significant portion of the patients included in this study developed HCC in conjunction with hepatitis B/C infection. When considering that this study examined patient outcomes before the widespread availability of agents to eradicate hepatitis C, it is likely that recurrence rates may improve after resection of highly-selected patients with multifocal HCC, further substantiating a role for resection in this population.

The concept of multicentric HCC (multiple primary tumors arising individually) versus intrahepatic metastatic HCC (one primary tumor with spread to other areas of the liver) has long been a subject of debate in the literature. While studies have shown that patients with multicentric HCC may have better outcomes, the difficulty lies in discriminating between the two processes.24 Some studies have used histologic grade to categorize them.24–26 Patients with multiple well-differentiated tumors may be classified as multicentric, while those with multiple tumors varying in degrees of differentiation (from well to poor) may be classified as intrahepatic metastases.24–26 In addition to tumor size, pattern of multifocal disease, and histologic grade, more recent studies are undertaking genetic analysis to see if these two processes can be better defined.17 Our findings support that patients with multifocal HCC who are also good surgical candidates (based on health status, size and location of tumors, planned resection) may benefit from a preoperative biopsy of their lesions. If well differentiated, our results suggest these patients may observe a similar survival to those who undergo resection for stage 1 disease. Perhaps, this subset of patients in our study actually represents those with multicentric HCC. In the future, texture analysis of imaging modalities (e.g. CT, MRI) may allow for physicians to predict grade, but at this time, we would recommend a biopsy in carefully selected operative candidates.27,28

This study carries with it limitations. First, given the retrospective nature of this review, there are missing variables and restrictions of data availability. For example, lymph/vascular invasion, alpha fetoprotein, and fibrosis scores were missing from a large percentage of patients, signifying that they could not be included in the multivariable analysis. A MELD score could not be included because the lab values listed in the NCDB are the highest lab value prior to treatment. We therefore have no means of assessing their baseline MELD and would run the risk of attributing an artificially high score if patients had abnormally high lab values that were not representative of their baseline (e.g. patients on anticoagulation). In addition, Child-Pugh class could not be calculated from the available data. However, given that this study was limited to patients who had already undergone surgery, it is likely that they were deemed appropriate surgical candidates and thus did not have major co-morbidities or extensive liver disease precluding an operation. Additional limitations included the absence of hepatitis status and recurrence data in this database. Due to these limitations, an analysis of what clinical factors may predict which patients have well differentiated tumors would not be reliable. Finally, the NCDB does not provide individual tumor sizes or the number of tumors for multifocal disease, therefore it is difficult to know if the patients who were resected fell under the Milan Criteria, University of California–San Francisco criteria, or Barcelona Criteria.29–31

We identified a subset of patients with multifocal HCC for whom resection may confer a similar survival benefit to that of patients with stage 1 disease. Currently, resection for multifocal HCC remains controversial due to the high risk of recurrence and therefore poor survival. Tumor grade may aid in the decision regarding resection (via pre-operative biopsy(ies)), or may alternatively be of prognostic value for those patients selected for operative management.

Funding

This work was in part supported by the intramural research program at the National Institutes of Health, National Cancer Institute, where some of the authors are employed.

Footnotes

Conflict of interest

The authors have no conflicts of interest to disclose. No external funding was provided for this study.

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