The optimal treatment for HCC is determined after careful consideration of the extent of disease as well as the overall condition of the patient, with special attention to baseline hepatic function. Primary tumor factors to consider include the size and number of lesions as well as the presence of vascular invasion,8–10
each of which is a component of the Milan criteria; adherence to these criteria has been shown to yield the best outcomes after transplantation.15
Along with assessing the oncologic appropriateness for resection, one must always consider the baseline status of hepatic function before proceeding with resection. There are a number of methods used to make a determination of the state of the liver, including the Child-Turcotte-Pugh score and the MELD score, as well as functional tests such as ICG clearance. The aim of this study was to assess the value of a low preoperative platelet count to independently predict postoperative morbidity and mortality in patients undergoing resection of HCC.
As the safety of liver surgery has improved because of better patient selection, intraoperative technique, and postoperative care, the extent and indications for resection continue to expand.5,6
However, the importance of tumor biology should not be overlooked when patients are selected for resection of HCC. Many investigators previously demonstrated poor outcomes associated with adverse tumor factors, such as large and multifocal tumors, presence of vascular invasion, and elevated α
The single best preoperative assessment of tumor biology still remains whether or not the tumor burden is within Milan criteria.15
Cha and colleagues20
reported similar outcomes between resection and transplantation for tumors that met Milan criteria, although patients who underwent resection in that series predominantly had solitary lesions. However, the regional variance between wait list times for organ availability still remains a major determinant of the appropriateness of transplantation.21,22
Given these considerations, resection remains one of the mainstays of treatment for HCC.
There is no single test that has emerged as the universal best assessment of preoperative liver function.23
One common functional test that is employed mostly in Europe and Asia is the ICG clearance test; however, this is rarely performed in the US. The Child score and MELD score are the 2 most commonly used assessment tools for determining hepatic function because both of these scores are a function of multiple individual parameters. An increasing MELD score is associated with increased perioperative mortality after general surgical procedures.24
One could extrapolate that the effect of a high MELD score on perioperative outcomes after liver resection would only be compounded. An elevated Child score is also associated with increased morbidity and mortality after liver resection.25
In fact, Child B status (score 7 to 9) is a relative contraindication for liver resection, especially for major hepatectomy.26
The overall performance status of the patient, as measured by the ASA class, is also a good predictor of postoperative outcomes after liver resection.25
Despite the comprehensive attempt to assess hepatic function, the widely used scoring systems discussed previously do not incorporate an assessment of portal hypertension. The routine invasive measurement of portal pressures is not practical for patients being considered for resection, and simple radiographic evidence of varices and splenomegaly is not adequate. Thrombocytopenia, however, is a good surrogate for the presence of portal hypertension in the patient population with HCC. The etiology of low platelet count can be multifold. For example, patients who have received extensive chemotherapy for liver metastases from colorectal cancer may have thrombocytopenia as a result of bone marrow suppression. However, in patients with HCC who have underlying liver disease, the etiology of low platelet counts is nearly uniformly secondary to portal hypertension–induced hypersplenism with increased platelet sequestration.
Although the presence of portal hypertension is not an absolute contraindication to liver resection and some have reported on the feasibility of resection in patients with severe thrombocytopenia (<50/nL),27,28
most investigators who have assessed this issue report increased morbidity and mortality in patients with a low preoperative platelet count who undergo resection. The mechanism for this association is likely secondary to worsening portal hypertension after resection, although alternate mechanisms have been proposed. Some have suggested that thrombocytopenia may greatly compromise the critical role that platelets have in the initiation of liver regeneration, as has been demonstrated in experimental rodent models.29
Two of the larger reported series of patients who underwent liver resection in which preoperative thrombocytopenia was found to be associated with poor perioperative outcomes included a heterogeneous population for whom resections were performed for a variety of different tumor types.5,6
As previously mentioned, the etiology of thrombocytopenia can vary, and thus its effect on outcome should ideally be assessed in a homogeneous patient population. Accordingly, Kaneko and coworkers30
reported in a retrospective analysis of 198 patients who underwent resection of HCC that preoperative thrombocytopenia was associated with increased postoperative mortality. This study, however, included patients over a 14-year period starting as early as 1990. Because hepatic resection has evolved tremendously since the 1990s in terms of operative technique and perioperative care, the relevance of their findings to current practice of liver resection may be questioned. Furthermore, the primary selection criteria used to assess adequacy for liver resection was ICG clearance, thus making their findings less applicable to practice in the US. Although ICG clearance was still used as the main selection criteria for extent of resection, other investigators from Japan have reported a more modern series of 213 patients who underwent resection of HCC between 1997 and 2002 in which a preoperative platelet count <100/nL was associated with an increased rate of postoperative complications (OR 4.6, 95% CI 1.5 to 14.3, p = 0.007).31
Similarly, Ishizawa and colleagues32
reported an increased incidence of large-volume ascites formation after resection in patients with preoperative platelet count <100/nL.
In the present series of 231 patients who underwent resection of HCC in the current era of liver surgery, a preoperative platelet count <150/nL was the only preoperative factor to be significantly associated with all 3 postoperative outcomes assessed, specifically major complications, PLI, and 60-day mortality. In this study, we sought to determine the independent value of a low preoperative platelet count when placed in the context of other common preoperative factors used to select patients for resection of HCC, namely Child score, MELD score, and tumor burden. Although an elevated ASA class and Child score as well as tumor burden beyond Milan criteria had varying predictive value, a low preoperative platelet count was the only factor that persisted in all 3 multivariate models (–). The cut-off point of 150/nL was determined based on receiver–operating characteristic analysis for the end point of PLI. This is clinically applicable given that 150/nL is the lowest value that still qualifies as a normal platelet count in most hospital laboratories. Furthermore, there was no significant difference in the poor outcomes of patients with a preoperative platelet count of 100 to 149/nL compared with those with a count of <100/nL.
There is no standard definition for what constitutes PLI. In an effort to create such a standard, Mullen and colleagues17
analyzed 669 patients who underwent hepatic resection for a variety of pathologies. They reported that a peak postoperative bilirubin level >7.0 mg/dL was the most powerful predictor of major complications and 90-day mortality. Given that the formation of ascites is also a clinical indicator of liver insufficiency, we incorporated this factor along with a peak bilirubin level >7.0 mg/dL into our definition of PLI. The postoperative INR value is often confounded by the transfusion of fresh frozen plasma, which was 22% in the current series, and thus this factor was not included in our definition of PLI.
Similarly, there is no standard for what defines postoperative mortality. Traditionally, 30-day mortality has been most commonly used, however, some suggest that 90-day mortality may be more appropriate for patients undergoing liver resection because death in the first few months may still be related to postoperative liver dysfunction. Mullen and colleagues17
found that the 90-day mortality was 4.7% compared with 3.2% for 30-day mortality, thus leading them to advocate for the longer time interval as a measure of postoperative mortality after hepatic resection. In the current series, we assessed 30-, 60-, and 90-day mortality and found that only 2 patients died within the 60- and 90-day intervals, whereas indeed there was a 50% increase in the number of patients who died between 30 and 60 days. Thus, for this study, we employed 60-day mortality as the standard for postoperative mortality because it may also potentially avoid any confounding 90-day deaths that occurred secondary to early uncontrolled recurrence.
When patients are selected for resection, the presence of hepatic encephalopathy is usually a contraindication to resection. In fact, in this series, only 3 patients (1.3%) had mild encephalopathy preoperatively. Thus, this factor most often does not contribute any value to the preoperative Child score assessment because nearly all patients being considered for resection have no encephalopathy; therefore, all got a score of 1 for this factor. In an attempt to modify and improve the utility of the Child score as a comprehensive assessment of the candidacy for resection, we replaced the factor of encephalopathy with the preoperative platelet count (1 = <100/nL, 2 = 100 to 149/nL, and 3 = ≥150/nL). Indeed, this modified Child score was significantly associated with major complications, PLI, and 60-day mortality on multivariate regression (–), and was the only factor that was significantly associated with PLI. The modified Child score was able to further stratify and identify those patients who had a prohibitive risk of morbidity and mortality after resection. Six patients were moved to a Child class C (score of 10 or 11); 50% of these patients developed PLI, and they had a 60-day mortality rate of 67%. Furthermore, the modified Child score seemed to better stratify the Child B patients. There was a decrease in the incidence of PLI and 60-day mortality in the patients classified as Child B based on the modified Child score compared with the traditional scoring system (). Thus, if the preoperative platelet count is preserved, it seems that the modified Child scoring system may better identify those select patients who may be offered resection with acceptable morbidity and mortality who otherwise would have been denied.
In summary, low preoperative platelet count is independently associated with increased major complications, PLI, and mortality after resection for HCC, even when accounting for standard criteria, such as Child/MELD score and tumor extent, used to select patients for resection. A modified Child score that incorporates the preoperative platelet count in place of encephalopathy may be a more appropriate preoperative assessment tool for selecting patients for resection of HCC. Patients with a low preoperative platelet count may be better served with either transplantation or liver-directed therapy.