Diagnostic and prognostic nomograms for bone metastasis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors and the fourth leading cause of cancer-related death worldwide, with 841,000 new cases and at least 780,000 deaths in 2018 [1]. Nowadays, surgical excision, liver transplantation, local administration of radiation or chemical drugs, and combined therapy are the main treatments for HCC patients [2]. However, most patients are diagnosed in the advanced stage. Therefore, the prognosis remains poor, and the 5-year survival rate was less than 20% [3]. Moreover, 14.0–36.7% of patients have distant metastasis at initial diagnosis [4, 5], and the prognosis was poorer in HCC patients with extrahepatic metastasis than patients without it [6].

Bone metastasis (BM) is a typical metastatic pattern in HCC patients. It was reported that the incidence of BM in HCC patients ranged from 3 to 20%, and showed a rising trend [3, 7‐9]. Although the management of HCC patients has improved in recent years, the prognosis of HCC with BM is abysmal, with a median survival of only 1–2 months [7]. Therefore, it is important to establish predictive models for predicting the BM in HCC patients and the prognosis in HCC patients with BM. In the previous studies, many risk factors and prognostic variables were identified, including SREs, AFP, Tomita scoring system, BMI, marriage status, and surgical treatment history of primary liver lesions [10‐14]. However, no researches focused on the predictive model for predicting the BM in HCC and the prognosis of HCC with BM, which means that the probability of outcome cannot be quantified.

Nomogram is a simple, multivariate visualization tool in oncology to predict and quantify the rate of the outcome of an individual patient [15], which were used to aid clinical decisions and promote the development of precision medicine. Therefore, based on the data from the Surveillance, Epidemiology, and End Results (SEER) database, we aimed to develop two nomograms for predicting the BM in newly diagnosed HCC patients and the cancer-specific survival (CSS) of HCC patients with BM, respectively.

HCC is an aggressive tumor and prone to extrahepatic metastasis, occurring in 14.0–36.7% of patients [20]. Meanwhile, the detection of extrahepatic metastasis from HCC increased because of the development of survival and diagnostic modalities [21]. Bone is a common site of extrahepatic metastasis, and the incidence ranges from 2 to 25% in HCC patients [12]. In our study, we established a diagnostic nomogram for predicting the BM in newly diagnosed HCC patients and a prognostic nomogram for HCC patients with BM. By obtaining the data of several easily accessible variables on the nomogram of each HCC patient, the total score can be calculated. Then, the risk of BM can be easily identified on the nomogram, which can provide guidance for further clinical management. Similarly, the prognosis of HCC patients with BM can be identified by prognostic nomogram. In our research, both nomograms demonstrated excellent performance in the risk assessment of BM and the survival prediction of HCC patients with BM, which will make the individualized clinical decision and surveillance more accurate.

Although the prognosis is extremely poor in HCC patients with BM, the early detection of BM could be crucial for HCC patients to receive appropriate therapy [22]. Therefore, it appears to be important for clinical decision-making to explore the risk factors for BM from HCC patients. In the molecular level, the expression of Chemokine receptor CXCR4 [23], MicroRNA-34a, [24] and LncRNA34a [25] were identified to be associated with BM in HCC patients. Nevertheless, these biomarkers were difficult and unpractical to apply immediately to clinical decisions. In addition, as for some practical clinical features, it was reported that marital status, T stage, N stage were risk factors for BM from HCC [12]. However, to date, no predictive model has been established, which means that the individual risk of BM cannot be identified by combining all independent BM-related predictors. In our study, the results showed that sex, grade, T stage, and N stage were the significant predictors for BM from HCC. The association between these factors and BM in HCC patients has been reported in previous researches. The association between tumor differentiation and TNM stage and BM in HCC patients has been confirmed in the previous study [26]. Another improvement of the nomogram was that the discrimination of nomogram was confirmed higher than any single predictors, which also showed the importance of a comprehensive predictive model.

In addition, our research showed that HCC patients with BM with lung metastasis, absence of chemotherapy, and absence of radiotherapy had unfavorable prognosis. Based on three independent prognostic factors, a nomogram was established. The results indicated that the nomogram can serve as an effective tool to identify high-risk patients. Similarly, the relationship between lung metastasis, chemotherapy, and radiotherapy and the prognosis in HCC patients have been widely reported in previous researches. In 2017, Yang et al. reported that multiple tumors and extrahepatic invasion were the independent adverse prognostic factors for HCC patients [27]. Therefore, as a common extrahepatic invasion site, patients with pulmonary metastasis were worse prognosis than patients without it. HCC with extrahepatic spread is considered to be in the advanced stage, and the therapeutic recommendation for this stage is oral sorafenib treatment [3]. Sorafenib had a positive effect on the survival of patients with advanced HCC [28]. Meanwhile, systemic chemotherapy with doxorubicin, gemcitabine or combined regimens for palliative care also improved HCC patients survival [3]. It was consistent with those reports that the absence of chemotherapy could lead to poor prognosis for HCC patients with BM and be an independent prognostic factor in our study. Generally, radiotherapy is a kind of treatment for uncomplicated symptomatic bone metastasis from HCC, aimed at palliation of symptoms [22, 29]. In the previous reports, radiotherapy was shown to provide effective palliation for patients with painful BM from HCC [9, 30]. In our research, radiotherapy showed favorable CSS in multivariate Cox regression analysis. Therefore, we recommend paying attention to the possibility of lung metastasis in patients with BM of HCC. For the sake of good prognosis, clinical treatment in HCC patients with BM could tend to be radiotherapy and chemotherapy. And further studies of significant prognostic factors for CSS in HCC with BM are necessary.

Our study showed that sex, grade, T stage, and N stage were the risk factors of BM from HCC. As for HCC patients with BM, lung metastasis, chemotherapy, and radiotherapy were independent prognostic factors for CSS. Two nomograms we created may be individual, convenient, and more intuitive visual tools for risk assessment and prognostic prediction for BM from HCC.