Tumor necrosis as a poor prognostic predictor on postoperative survival of patients with solitary small hepatocellular carcinoma

As the second leading cause of cancer mortality worldwide, hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence especially in Southeast Asia and Africa, with an increasing incidence in Europe and America [1‐3]. Because of the persistent prevalence of hepatitis B virus (HBV) infection, HBV-related liver cirrhosis and/or HCC has become a main disease burden in China [4]. Currently, early detection and surveillance allow for the discovery of more small HCCs (sHCC, ≤ 3 cm in diameter) [5, 6].

Solitary sHCC is a special type of HCC with favorable long-term outcomes [7, 8].. Albeit surgical resection provides potentially curative therapies, disease recurrence is still frequently found in many patients postoperatively and less is known about the factors correlated with aggressive biological phenotype of sHCC [5‐8]. It may be ideal to identify patients at high risk of tumor recurrence and/or poorer outcome, and to target close follow-up or postoperative adjuvant therapies in these sub-populations [9, 10]. Currently, the known clinicopathological factors for sHCC enable the identification and screening the patients at high risk, however, the reliable factors remain ill-defined [11, 12].

Traditionally, pTNM stage and histological grading systems are recognized as the most useful prognostic factors of sHCC. In addition, other features such as tumor size and vascular invasion are also utilized in clinical setting and found to be prognostic assessment of sHCC patients. Tumor necrosis is a common pathological feature of solid tumors, which is documented to be correlated with chronic ischemic injury due to the rapid growth of tumor [13‐15]. The extent of tumor necrosis reflects the level of intra-tumor hypoxia. What’s more, increased cellular hypoxia is linked to the increased metastatic potential and worse outcome in solid tumors, as well as resistance to radio-chemotherapy [13, 16]. To date, the clinical and prognostic implication of tumor necrosis in solitary sHCC remain elusive [17, 18]. In the present study, we proposed to assess the prognostic value of tumor necrosis in solitary sHCC following hepatectomy and to demonstrate whether tumor necrosis can be regarded as a parameter for sHCC aggressiveness. In addition, we further aimed to construct a clinicopathologic model with risk factors to predict the prognosis of sHCC patients.

In the current study, we assessed a retrospective collection of data and determined the prognostic value of tumor necrosis for pathologically proven sHCC patients. Tumor necrosis was frequently observed and a prognostic factor independent of certain well-established clinical factors, including tumor size, vascular invasion, serum AFP level and clinical stage in sHCC. Notably, we found that tumor necrosis, vascular invasion and tumor size were poor prognostic factors. Further analysis evaluated that tumor necrosis was significantly associated with vascular invasion in sHCC.

Tumor necrosis has been shown prognostic impact in lung, breast, thyroid, colorectal, pancreatic, and kidney malignancies, but also in mesenchymal tumors, such as malignant mesothelioma, gastrointestinal stromal tumors and Ewing sarcoma [13, 14, 16, 23‐26]. Moreover, Soini et al. reported that the survival of sHCC patients showing a high proliferation and simultaneously a low degree of apoptosis and necrosis was significantly shorter [17]. Martino et al. found that the non-cirrhotic HCC patients may presented with certain areas of necrosis but did not demonstrate the relative prognosis [18]. Thus, data regarding the incidence and prognostic impact of necrosis in sHCC remain limited. Our research has characterized and demonstrated for the first time that tumor necrosis predicts poor survival in sHCC, which implies a relationship that increased tumor cell death indicates a more aggressive cancer. Tumor microvessels are fragile and susceptible to hypoxia, suggesting that the degree of tumor necrosis reflects the level of intratumoral hypoxia [13, 14, 27, 28]. Intratumoral hypoxia has been reported to correlate with poor prognosis and sensitive to radiotherapy and chemotherapy in solid tumors with a polarographic needles [13]. In breast cancer, tumor necrosis has been shown to correlate with increased tumor size, high-grade disease, high microvessel density, and infiltrates of macrophages that express vascular endothelial growth factor, suggesting that hypoxic environment causing tumor necrosis stimulates angiogenesis owing to angiogenic growth factors released by infiltrating macrophages in rapidly growing tumors [23, 29, 30].

Vascular invasion is found to be related to decreased overall and recurrence free survival in post-surgical resection and transplant HCC patients [31, 32]. Our previous study revealed evidence supporting that vascular invasion had an adverse impact on long-term survival in sHCC patients [22]. The association of tumor necrosis and vascular invasion in the current study is consistent with studies in breast cancer and malignant mesothelioma, in which it was also observed that microvessel hot spots were situated away from areas of tumor necrosis [23, 33]. It can be reasonably explained this paradoxical relationship that because of tumor rapid growth the microvasculature is ischemic damaged due to its supply overload and thereby increasing tumor necrosis. Tumor size is a well-known risk factor for poor survival of solid tumor. In breast cancer, tumor necrosis correlated with increasing tumor size [23]. It was also confirmed that increasing mass was associated with hypoxia in the experimental murine allograft model [34]. Similarly, we previously demonstrated that tumor size > 2.5 cm was correlated with a worse OS or RFS and tumor necrosis was associated with increasing tumor size in the sHCC patients [22].

According to the clinical practice guideline, surgical resection is recommended in early stage HCC [35]. However, sHCC patients still suffer from tumor recurrence due to various intratumour heterogeneity of the patient population. Traditionally, the pTNM Staging and grading system have been utilized to determine the treatment and the prognosis of solid tumors. Nevertheless, based on specific clinicopathologic features and extent of disease, this system might have their limitation for sorting out high risk of tumor recurrence populations from early-stage HCC patients and offering clear pathways to help novel follow-up strategies and salvage therapy. Thus, there is a need for new objective strategies that can effectively distinguish between sHCC patients with favorable and unfavorable outcome. By far, in renal cell carcinomas, the presence of tumor necrosis has been proposed to be incorporate into grade classification system [36]. In our present study, when OS and RFS rates were compared between patients with and without tumor necrosis, significantly poorer prognosis could be observed for those with tumor necrosis in one large population-based cohort of sHCC patients, supporting the concept that tumor necrosis adds additional prognostic information and could further stratify patients with or without aggressive clinical course and/or adverse outcome. In addition, we proposed a combined prognostic model with tumor necrosis, tumor size and vascular invasion and found that the model may be a useful prognostic index to reflect the aggressive phenotype for sHCC. Generally, our findings support the idea that the pTMN supplemented by tumor necrosis, vascular invasion and tumor size might improve the ability to discriminate sHCC patients’ outcome, along with the effectiveness of personalized and precise treatment.

The retrospective nature of this study may be considered its major limitation. There are also strong efforts to integrate biomarkers into established clinicopathologic models to further improve their predictive ability. However, our study was strengthened by the fact that all of the histopathological slides were re-evaluated by two gastrointestinal pathologists. Although, we believe that our results contribute to the literature because it includes only patients with sHCC.

In summary, our findings demonstrated that tumor necrosis could be used as an additional effective predictor in identifying those patients at increased risk of tumor progression. The proposed new prognostic model (combined tumor size, vascular invasion and tumor necrosis) might improve the ability to discriminate sHCC patients’ outcome, along with the effectiveness of personalized and precise treatment in the future.