Tumor Size, Not Small Vessel Invasion, Predicts Survival in Patients With Hepatocellular Carcinoma

Dongwei Zhang, MD, PhD; Tanzy Love, PhD; Yansheng Hao, MD, PhD; Bella Lingjia Liu, MD; Swan Thung, MD; Maria Isabel Fiel, MD; Christa L. Whitney-Miller, MD; Xiaoyan Liao, MD, PhD


Am J Clin Pathol. 2022;158(1):70-80. 

In This Article

Abstract and Introduction


Objectives: The 8th edition American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) has been criticized for failing to stratify patients. We aimed to reassess and modify the tumor staging criteria for HCC.

Methods: Three independent study cohorts were collected and analyzed.

Results: The initial cohort consists of 103 patients with HCC. By Kaplan-Meier survival analysis, the 8th edition failed to distinguish between T1b and T2. Only tumor size and large vessel invasion, but not small vessel invasion or other histopathologic parameters, predicted HCC survival. We modified the T staging criteria by eliminating small vessel invasion while emphasizing tumor size in the middle categories (T2 and T3), which achieved more even distribution of cases and significantly improved risk stratifications (P < .001). This modification was then validated in a cohort of 250 consecutive patients from Mount Sinai Hospital and an online Surveillance, Epidemiology, and End Results data set comprising 9,685 patients, which showed similar results. Small vessel invasion was not an independent prognostic factor in either validation cohort.

Conclusions: Our study showed that tumor size, but not small vessel invasion, predicts survival in patients with HCC. We suggest incorporating our modified T staging criteria in future AJCC revisions.


Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver, the fifth most common malignancy worldwide, and the third leading cause of cancer-related deaths globally.[1,2] HCC can be attributed to many different risk factors, such as viral hepatitis, metabolic disorders, or toxins.[3–5] Current treatment choices include tumor resection, liver transplantation, radiofrequency ablation, and transcatheter arterial chemoembolization.[6,7] Optimal management remains controversial owing to the heterogeneity of HCC and underlying liver diseases.[2,8] It is essential to provide accurate pathologic analysis and tumor staging for patients with HCC, which should correlate directly with risk stratification, prognosis prediction, proper clinical management, and follow-up. Several staging and scoring systems can predict the clinical outcomes of HCC,[9] among which the American Joint Committee on Cancer (AJCC) TNM staging system is widely accepted and most frequently used.[10–12]

The 8th edition of the AJCC Cancer Staging Manual is the current version and has been in use for approximately 3 years.[13] Compared with the 7th edition, the 8th edition includes substantial changes for HCC regarding the T criteria, although the N criteria remain the same. Briefly, T1 is subdivided into T1a and T1b based on a tumor size cutoff of 2 cm, where T1a includes solitary tumors 2 cm in size or smaller regardless of vascular invasion, while both T1b and T2 include solitary tumors greater than 2 cm, but T2 is distinguished from T1b by the presence of vascular invasion. In the 7th edition, T3 was subdivided into T3a (multiple tumors, at least 1 greater than 5 cm in size) and T3b (tumors involving a major branch of the portal vein or hepatic vein). The 8th edition does not subdivide T3: the previous T3a is now T3, and the previous T3b is upstaged to T4. Those changes were incorporated into the 8th edition based on a few studies performed in Asia, which has the largest population of patients with HCC because of the high prevalence rate of hepatitis B virus infection.[12]

Since its publication, this newest AJCC staging manual was criticized by several studies in Asia and Europe as well as studies using the online Surveillance, Epidemiology, and End Results (SEER) database, which suggested that the 8th edition performed similarly to or not better than the 7th edition.[14,15] Besides anatomic criteria, many researchers explored the possibilities of other histologic or biological parameters for prognostic significance and staging potential. For example, some found that macrotrabecular HCC, glypican-3 expression, and certain HCC subtypes may be associated with better or worse disease outcomes.[16–18] A recent study identified differentially expressed stage-specific genes in HCC that may enhance our understanding of the molecular determinants of HCC progression and serve as biomarkers that potentially underpin diagnosis and therapeutic targets.[19]

The aims of this study were fourfold: first, to comprehensively characterize the clinicopathologic and immunohistochemical features of HCC in an initial study cohort at our institution (University of Rochester Medical Center [URMC]); second, to assess the 8th edition AJCC T staging criteria compared with the 7th edition and evaluate the prognostic value of other histopathologic parameters on HCC survival in the initial study cohort; third, based on the results of the first and second aims, to propose modifications of the T staging criteria with improved prognostic functions, offering suggestions for future revisions; and fourth, to validate the proposed modifications in an independent study cohort from Mount Sinai Hospital (MSH) in New York and a large SEER database queried between 2010 and 2015. To achieve the best result in the initial study cohort, we strictly selected cases by slide review, careful chart review, and matched tissue microarray analysis for each case.