For patients with hepatobiliary malignancies, various therapeutic options are currently available. To optimize the selection of these treatment options, adequate stratification of patients according to their prognosis is practically important. Various staging systems have been introduced and used for hepatobiliary malignancies. However, current staging systems have strengths and limitations, and none have addressed both patient prognosis and the best treatment strategy for individual patients. Hepatic function is also a potent prognostic factor for patients with hepatobiliary malignancies. Therefore, interpretation of tumor staging and selection of treatment should be done with care, understanding individual characteristics of each staging system.
Key points
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Tumor staging is important for stratifying patients according to prognosis and selecting adequate treatment options.
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A variety of staging systems are available for hepatobiliary malignancies. However, each staging system has its own strengths and weaknesses, and no perfect staging system exists.
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Patients with hepatobiliary malignancies often have decreased hepatic function from underlying liver disease.
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Tumor staging should be interpreted with care according to the status of patients, while understanding of the nature of each staging system.
Introduction
For patients with hepatobiliary malignancies, various therapeutic options are currently available, including surgical resection, ablation, transarterial chemoembolization (TACE), systemic therapy, and radiotherapy. To optimize the selection of these therapeutic options, adequate stratification of patients according to their prognosis is practically important. Among the hepatobiliary malignancies, hepatocellular carcinoma (HCC) is the most studied malignancy, and various staging systems have been proposed from both clinical and pathologic standpoints, such as the Cancer of the Liver Italian Program (CLIP) score, Barcelona Clinic Liver Cancer (BCLC) staging system, Liver Cancer Study Group of Japan (LCSGJ) staging system, or American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging system. However, these staging systems have their relative strengths and weaknesses. In addition, for biliary tract cancers, several controversies remain regarding prognostic implications of tumor location or definition of regional lymph nodes. This article reviews currently used staging systems for hepatobiliary malignancies, and highlights their clinical relevance and controversies.
Staging of primary liver cancer
HCC
CLIP score
The CLIP score was developed using data on 435 Italian patients with HCC treated with a range of surgical and nonsurgical therapies ( Table 1 ), and several subsequent validation studies confirmed the clinical relevance of this prognostic score. The CLIP score includes more tumor-specific factors and offers better prognostic stratification than the conventional Okuda Staging System, which included tumor morphology, presence of ascites, serum albumin level, and serum bilirubin level as parameters for prognostic scoring. However, the limitation of this staging system is its poor discriminatory power of prognosis in early and advanced stages of HCC. The parameter of tumor morphology includes a wide range of tumor sizes. Furthermore, vascular invasion, which is a potent prognostic factor for HCC, is not considered unless a portal vein tumor thrombus is present. Therefore, the clinical use of the CLIP score is limited, especially in the selection of therapeutic options.
| Points | |||
|---|---|---|---|
| Variable | 0 | 1 | 2 |
| Child-Pugh grade | A | B | C |
| Tumor morphology | Solitary and ≤50% | Multifocal and ≤50% | Massive or >50% |
| Serum α-fetoprotein | <400 ng/mL | ≥400 ng/mL | |
| Portal vein thrombosis | Absent | Present | |
BCLC staging system
The BCLC staging system ( Fig. 1 ) is one of the popular staging systems, especially in European countries. This system includes liver function, tumor characteristics, and performance status when addressing disease progression, and offers adequate therapeutic options based on the treatment algorithm. Although its usefulness was validated in several studies, one of the major drawbacks of this staging system is that it is based on a single institutional experience. Furthermore, mixture of staging system and treatment algorithm may cause several problems in actual clinical settings. First, the surgical management is rather conservative in this system, and patients with lesions greater than 5 cm are not candidates for surgery. Because treatment for HCC has been changing over time and some patients actually benefit from multidisciplinary and/or sequential approach (eg, resection after TACE plus portal vein embolization, or orthotopic liver transplantation after TACE), simplified therapeutic recommendations for each tumor stage do not fit with actual clinical practice. Second, although the BCLC staging system considers both underlying liver disease and cancer progression, this system is rather a treatment algorithm than a pure cancer staging system, and accordingly, simple comparison with other staging systems is difficult.
LCSGJ staging system
The LCSGJ 4th edition staging system was developed by a working group of the International Hepato-Pancreato-Biliary Association using data on 21,711 Japanese patients who underwent liver resection for HCC. T factor is determined based on how many of the following factors are present: tumor size (≤2 cm or >2 cm), tumor number (solitary or multiple), and macrovascular invasion (present or absent). The stage is determined according to the T factor and presence of regional node metastasis (N) or distant metastasis (M) ( Table 2 ). The strength of this staging system is that it is based on a large cohort from a Japanese nationwide survey by the LCSGJ. However, the limitations are that this staging system places equal weight on each of 3 tumor-specific factors, and only macroscopic evidence of vascular invasion is accounted for in determining T factor.
| T | T1 | None of following factors |
| T2 | One of following factor | |
| T3 | Two of following factors | |
| T4 | Three of following factors or tumor rupture/direct invasion | |
| ||
| Stage I | T1N0M0 | |
| Stage II | T2N0M0 | |
| Stage III | T3N0M0 | |
| Stage IVA | T4N0M0 or T1–3N1M0 | |
| Stage IVB | Any T/N, M1 | |
AJCC/UICC staging system
The AJCC/UICC 7th edition TNM staging system is a modification of the simplified TNM staging system based on a study from the International Cooperative Study Group on Hepatocellular Carcinoma that included data on 591 surgical patients from the United States, Japan, and France ( Table 3 ). The strength of this staging system was the use of centralized pathologic review, and its clinical relevance has been validated in various subsequent studies in patients treated with liver resection. Validation was also performed using patients who underwent transplant in a multicenter study. Because liver explantation enables complete removal of liver invaded by cancer, full staging of HCC is feasible depending on the progression of the initial cancer.
| T | T1 | Solitary with no vascular invasion |
| T2 | Solitary with vascular invasion or multifocal ≤5 cm | |
| T3a | Multifocal >5 cm | |
| T3b | Involvement of a major branch of the portal vein or hepatic artery | |
| T4 | Invasion of adjacent organs or rupture of HCC | |
| Stage I | T1N0M0 | |
| Stage II | T2N0M0 | |
| Stage IIIA | T3aN0M0 | |
| Stage IIIB | T3bN0M0 | |
| Stage IIIC | T4N0M0 | |
| Stage IVA | Any TN1M0 | |
| Stage IVB | Any T/N, M1 | |
However, the limitation of the current edition of the AJCC/UICC staging system is that solitary HCC is not stratified with respect to size. Recent studies have reported excellent long-term outcomes in patients with solitary HCC up to 2 cm. The size cutoff of 2 cm has been adopted in the LCSGJ and BCLC staging systems. Although the presence of microvascular invasion has been reported to be a strong prognostic factor in HCC, its significance in small HCC has not yet been clarified.
A recent study from the International Cooperative Study Group on Hepatocellular Carcinoma reported that microvascular invasion does not affect patient prognosis in small HCCs up to 2 cm, and showed the potential for the reclassification of the current version of the AJCC/UICC staging system ( Fig. 2 , Table 4 ). This result is practically important because various curative therapeutic options can be selected for small tumors up to 2 cm, and also suggests that resection for the purpose of pathologic evaluation might not be necessary in patient selection for liver transplantation.
