The last decade has experienced a steady increase in the incidence of MPM . With the expected survival of oncology patients prolonged, it is no longer rare to observe a subsequent primary malignancy in long-term follow-up, especially those from therapy-related carcinogenesis [17, 18]. A recently published paper provided by the Surveillance, Epidemiology and End Results Program estimated 7.9% of cancer-survivors were living with a history of more than one primary malignancy in the U. S . The reported prevalence estimated that cancer-survivors were at an increased risk of being diagnosed with a secondary primary malignancy [19–21]. Bhatia et al. showed the risk of second tumor was increased approximately 18 times in survivors of childhood Hodgkin’s lymphoma . The incidence of second neoplasm in cancer-survivors (2.3%, 68/2909) of our center was in accordance with previous literature [6, 16, 22, 23], which was higher than that of the normal population . We hypothesized that the improvement in early screening technologies, the advent of new molecular targeted agents, and elevated risk of carcinogenesis during the anti-cancer therapy yielded an increase prevalence of second cancer in the individuals ever diagnosed malignancy.
Several studies have demonstrated that the risk factors for poor survival of MPM patients, including male, elderly, and tumor stage [11, 24]. While, our study showed no statistical difference for OS was observed in conventional clinicopathological parameters, which was agreed with other studies [5, 23]. This discrepancy may be due to the different disease etiologies and heterogeneity of study populations. We believe that a study of patients from a large, multicenter, and multigeographic area would reach conclusions more powerful.
A unimodal distribution of interval time among the prior and post subgroups of the metachronous group was shown in Figure 1. Based on the time since the first cancer diagnosis, the overall risk was decreased following the first 2 years. Considering that most secondary cancers were detected by periodic examination, a postoperative periodic checkup should be performed intensively both for the prior and post groups, especially during the first 2 years. Interestingly, we found that an obvious predominance exhibited in the prior group. We hypothesized that the poor prognosis of HCC may explain partially to this circumstance .
Information regarding the common sites of EHMP may benefit the detection of high-risk individuals via early diagnosis, leading to improve cancer-survivor outcome. Therefore, we analyzed the frequency of EHPM according to tumor types. Contrary to our expectations drawn from the results of previous studies conducted in Japan  and Western countries , nasopharynx cancer ranked first in extrahepatic tumors, not gastric nor colorectal cancer. Nasopharyngeal carcinoma (NPC) is a disease with remarkable geographic distribution and a high incidence rate in South China. However, despite its prevalence, it does not rank first among extrahepatic tumors in South China . The reasons for the high incidence of NPC in HCC patients are unclear. No apparent environmental  or shared genetic factors  explained the circumstance. In light of the high frequency of NPC in EHPM, head and neck screening (physical examination and flexible laryngoscopy) should be considered in those patients. These data suggest oncologists should be aware of the risk of secondary tumor development if unexpected symptoms or signs appear, as intensive follow-up may benefit early diagnosis.
A differential diagnosis of HCC should be made, as the liver being one of the most common sites of metastases. In our cohort, 30 HCC patients were diagnosed via standard clinical and imaging criteria combined with an elevated AFP level. The characteristic of HCC imaging in the MPMs was similar to that of HCC-alone patients. Dynamic CT can provide useful information for the differential diagnosis for hepatic nodules . A metachronous patient presented two hepatic nodules after NPC radiotherapy in this study. CT imaging showed two nodules with distinct radiologic natures (one with typical presentation of a low-density mass in the plain CT, which changed to a high-density mass in the arterial phase with relative low density in the delayed phase of dynamic CT; the other presented metastatic cancer: enhance less intensively and washout more slowly). Postoperative pathology confirmed the case suffered hepatoma complicating hepatic metastases from NPC.
We investigated whether cancer-survivors would experience poorer prognoses after second malignant neoplasm diagnosed. Our study showed that the difference of HCC-specific survival between MPM involving HCC and HCC-alone failed to reach statistical significance. This finding was similar to that reported in several cohorts [2, 23], and reflected differences in the natural course of HCC compared with most associated EHPM. HCC is always associated with a poorer survival and a more aggressive behavior than most other tumors. Several cohort studies noted that the causes of death in HCC patients with EHPM were mostly attributed to HCC itself, not to extrahepatic cancer [3, 5]. In light of these data, we stressed the need to prioritize curative treatment for HCC independently of the EHPM, as the presence of an EHPM had little impact on HCC-specific prognosis. While, we noticed that no significant difference was observed in overall survival between surgery and other therapeutic options for HCC. A long-term diagnostic interval time (median 32.4 months) from the diagnosis of the first neoplasm to the subsequent tumor presumably influenced the impact efficiency of treatment options for HCC on overall survival.
A significant difference in OS between the patients in the metachronous group and the synchronous group was not surprising. Compared with metachronous patients, synchronous patients had poorer OS. As demonstrated in Table 3, synchronous and metachronous groups associated with different treatment approaches for the extrahepatic tumor, and different treatment strategies led to distinct outcomes. Thus, we suspected that treatment modality was the final influencing factor for overall survival and built a Cox multivariate model for verification. Cox analysis confirmed it and demonstrated that treatment options for extrahepatic cancer remained as the significant factor. Therefore, an increasing effort to enlarge the proportion of patients undergoing radical treatment should been taken into account, irrespective of synchronous or metachronous tumor development.
Curative resection, if possible, most effectively prolongs patient survival. However, in cases of HCC with EHPM, the choice of treatment strategy should be made carefully in conjunction with the treatment for EHPM. There are few reports on how to treat patients with MPM involving HCC, which remains a key challenge. In our cohort, hepatectomy was an independent prognostic factor associated with good outcome. In spite of the patients that had a cirrhosis background, as experienced in our center, when patients had well-preserved liver function and when there was also an absence of extrahepatic metastasis, aggressive liver resection provided an opportunity for long-term survival.
MPM patients including HCC were often treated with supportive treatment, due to the limited therapeutic options, disappointed radical surgical rate, and poor prognosis of HCC . Although several papers reported MPM concomitant with surgical HCC patients [2–5, 23, 24], with the small number of patients, the statistical power was limited. Of noted, only two cohort studies investigated the influence of EHPM on survival with more than 20 surgical HCC [2, 3]. Furthermore, both of the two papers failed to refer to HCC-specific survival, which lead to decrease the value for clinical practice. We believe the present study may provide powerful evidence to make therapeutic strategy for MPM patients with HCC, which suggest those patients should not be excluded from radical resection for HCC.
Potential limitations of our study are the long time span of the observed data and the relatively small sample size, particularly with only 35 MPM patients with resected liver tumors. It would be more powerful the results from multicenter studies with larger numbers, considering the different geographic distribution of HCC. Nonetheless, the consistency of our findings with previous clinical surveys reinforces the validity of our conclusions.