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Validation of P2/MS for reflecting hepatic fibrosis in patients with hepatocellular carcinoma

Background/Aims P2/MS is known as a simple, accurate, and noninvasive marker for determination of the degree of hepatic fibrosis in patients with viral hepatitis. We aimed to validate P2/MS in patients with HCC. Methods Consecutive HCC patients who underwent surgical resection between June 2007 and March 2009 at Seoul National University Hospital were enrolled. Fibrosis stage was reviewed and assessed according to METAVIR scoring. P2/MS values [platelet count (109/L)]2/[monocyte fraction (%)×segmented neutrophil fraction (%)] and other noninvasive fibrosis scoring systems were calculated. Results A total of 171 patients were included; seven patients with METAVIR F1, 31 with F2, 41 with F3, and 92 with F4. The area under the receiver-operating characteristic curve of P2/MS was 0.804 [95% confidence interval (CI), 0.681~0.927] for detection of significant fibrosis (F2-F4) and 0.769 (95% CI, 0.698~0.839) for detection of histological cirrhosis (F4). At a value < 62, P2/MS detected significant fibrosis with a specificity of 85.7% (95% CI, 42.0~99.2) and a positive likelihood ratio of 4.268 (95% CI, 0.692~26.309); and at a value > 115, P2/MS ruled out significant fibrosis with a sensitivity of 90.2% (95% CI, 84.4~94.1) and a negative likelihood ratio of 0.34 (95% CI, 0.106~0.095). P2/MS had a superior efficacy for detection of hepatic fibrosis in patients with HCC compared to the other noninvasive panels. Conclusions P2/MS can accurately detect fibrosis in patients with HCC. Thus, P2/MS might be utilized as a noninvasive index reflecting the degree of hepatic fibrosis in HCC patients.


INTRODUCTION
Chronic hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC). 1 Although it has been reported that up to 40% of HBV-related HCC develops in patients who do not have cirrhosis, almost all cases of chronic hepatitis C virus (HCV) related HCC occur in cirrhotic liver. 1 In most cases of HCC which originate from cirrhotic liver, hepatic fibrosis might be one of the early changes of hepatocarcinogenesis because cirrhotic changes of the liver could be resulted from accumulation and exacerbation of fibrosis. 2 On the other hand, it has been demonstrated that HCC patients with advanced fibrosis had shorter overall survival periods than those without it. 3 The fibrosis score is recommended for tumor-node-metastasis staging of HCC. 4 In addition, the Barcelona Clinic Liver Cancer (BCLC) classification integrated several prognostic factors including portal hypertension which is related to hepatic fibrosis. 5 Therefore, the accurate evaluation of hepatic fibrosis is necessary not only for determining the plan of antiviral therapy but also for the prognostic value in patients with HCC. The gold standard for assessment of hepatic fibrosis has been liver biopsy. 6 However, over-or underestimation of fibrosis can be possible due to intra-and interobserver variability and sampling errors. 7,8 Several limitations, such as invasiveness, risk of complication, and the availability of expert practitioners, hamper the clinical use of liver biopsy especially when repeated tests are required. 9 The current diagnostic strategy for HCC mostly depends on imaging modalities without liver biopsy. 10 Assessment modalities of hepatic fibrosis status without biopsy are required to help predict the prognosis of patients with HCC. Consequently, alternative noninvasive methods based on imaging studies 11,12 and biochemical tests [13][14][15][16]    AST to ALT ratio (AAR)=AST/ALT

Histological examination of liver tissue
The liver surgical specimens were fixed in formalin and embedded in paraffin. Hematoxylin and eosin (H&E) and Masson's trichrome staining were performed. Histological examinations were carried out by an experienced liver pathologist who was blinded to any clinical information. Fibrosis stage was reviewed and assessed in non-tumorous liver parenchyma according to the METAVIR scoring system. 24 Fibrosis was staged on a scale of 0~4

Patient characteristics
The patient characteristics are summarized in Table 1 (Fig. 2). The sensitivity, specificity, PLR, and NLR of P2/MS were calculated using previously published cut-off values (

Comparison of P2/MS and other noninvasive fibrosis scoring systems
Mean values of noninvasive fibrosis scoring systems were summarized in Table 3. To evaluate the diagnostic value of noninvasive fibrosis scoring systems for significant fibrosis, we compared the AUROC of P2/MS with those of other tests ( Table 4) Table 5).

DISCUSSION
The principal findings of this study relate to the detection of significant hepatic fibrosis of patients with HCC by P2/MS. For histological cirrhosis (METAVIR F4), the diagnostic accuracy was greatest for P2/MS among noninvasive fibrosis scoring systems and there was a statistically significant difference between that of P2/MS and AAR.
The early detection of hepatic fibrosis is important for predicting clinical outcomes of patients with HCC. 4 In addition, hepatic fibrosis is a determinant factor for the antiviral therapy strategy in patients with HBV replication and raised ALT levels, or those with high normal ALT levels and who are older than 40 years. 25 However, the current gold standard for the diagnosis of hepatic fibrosis is a liver biopsy which has several disadvantages, such as poor compliance, invasiveness, complications, and cost. 9 Therefore, noninvasive modalities of evaluating hepatic fibrosis have been proposed to overcome these problems. The two principal categories of noninvasive tests include serum fibrosis panels and hepatic elasticity imaging. 23 However, these modalities have not showed sufficient diagnostic efficacy for complete replacement of liver biopsy. 18 In the meantime, P2/MS, a new, accurate method, based only on a complete blood cell count, was developed for reflecting significant fibrosis (METAVIR F2-F4) and cirrhosis (METAVIR F4) in virus-related CLD. 17