The present study has revealed that secondary OSCC patients underwent radiotherapy for head and neck cancer show poor survival outcomes, and the prognostic of squamous cell carcinoma in oral cavity with a history of radiotherapy was not in accordance with its sporadic counterpart. Margin status is an independent prognostic factor of second primary OSCC.
Complete resection with tumor-free margins is a key goal of oncologic surgery. However, our clinical experience has suggested that it is difficult to identify tumor border in OSCC patients with a history of radiotherapy due to changes in the soft tissue and chronic oral mucosal inflammation after radiotherapy. Occasionally, there is an initial cut-through of the invasive tumor at the surgical margin. Although additional adjacent tumor-free margins are achieved, the risk of local relapse is still high[12]. In the present study, additional adjacent tumor–free margins are achieved in all cases, and margin status is found to be an independent prognostic factor of OS in patients developed second primary OSCC and it is also significantly associated with DFS. Thus, it is important to determine the border of the secondary tumor and achieve a clear margin in surgery in these patients.
The presence or absence of ENE is used to assign N category in AJCC 8th edition in head and neck SCC. ENE is defined as tumor extension through the lymph node capsule into surrounding connective tissues[13]. ENE is found to be significantly associated with OS.
Lifestyle factors such as tobacco and alcohol abuse may have a negative impact on OS[14, 15]. In this study, there is no significant association between lifestyle factors (alcohol consumption and smoking) and the survival of patients. However, it is important to note that we could not obtain an accurate record of smoking in pack-years and the number of alcohol consumption days per week or the amount of drinking per day.
Ionizing radiation is a well-known risk factor of malignant tumors. Previous studies on second primary tumors in the head and neck region induced by radiotherapy have mainly focused on NPC survivors. However, we have also found in clinical practice that patients underwent radiotherapy for head and neck cancer could have tumors in the oral cavity, major salivary gland, and nasal cavity. Thus, non-NPC survivors should also be considered in investigating the outcomes and clinicopathological characteristics of second primary OSCC. A recent study including some non-NPC survivors in second primary tumor patients has focused only on specific gingival squamous cell carcinoma[6]. To the best of our knowledge, this is the first study on the prognosis of second primary OSCC in both NPC and non-NPC survivors with a history of radiotherapy for head and neck cancer.
It has been reported that the survival outcome is better in patients with sporadic oral cancer than in patients with a history of radiotherapy for head and neck cancer. Zhang et al[7] and Sun et al[16] investigated the prognosis of tongue squamous cell carcinoma with a history of radiotherapy for NPC. Dai et al[5] showed that second primary OSCC had a worse outcome than sporadic OSCC in NPC survivors. In the present study, the 5-year OS of patients with secondary OSCC is 39.4%, which is much worse than those with sporadic lesions reported in literature.
It is also noted that the sites differ between sporadic oral cancer and second primary tumor in patients with a history of radiotherapy. The most frequent sites of second primary tumor are the tongue, gingiva and bucca, while those of sporadic lesions are the tongue, gingiva and hard plate[6].
We have found that the prognosis of second primary oral cancer is not in accordance with the clinical stage of AJCC staging system on OSCC. Patients with stage Ⅱ, Ⅲ and Ⅳ lesions show similar OS. The patients with clinical stage Ⅰ had a trend of better prognosis than other stages (significance was reached comparing stage Ⅰ and Ⅲ, p = 0.018, log-rank = 5.588). Fu et al.[6] found that some clinicopathologic characteristics, such as prominent sites and TNM stage, were significant prognostic factors of second primary gingival squamous cell carcinoma after radiotherapy. Thus, the prognostic factor of secondary OSCC may be different from that of sporadic OSCC.
It is difficult to select the cases with secondary tumors caused by radiotherapy and make critical distinction between tumors caused by radiotherapy and sporadic tumors arising after radiotherapy. In all of the previous investigations on secondary malignant tumors, there was no exact method to distinguish secondary tumors from sporadic except by criteria based on reviewing the history of radiation. Although it is difficult to make critical distinction of tumor caused by radiotherapy and tumor can occur without radiotherapy involved, it is important to investigate the difference between malignancy with and without a history of radiotherapy in oral and maxillofacial region. In the present study, we analyzed the patients with a history of radiotherapy involving the region of secondary tumors, following the criteria established by previous investigators of selecting the secondary tumors with the greatest extent possible.
Previous studies have shown no significant difference in OS between patients received surgery and those received comprehensive treatment based on surgery[5, 16]. There might be a bias, for comprehensive treatment was much more probable considered when the tumor was in more advanced stage. In this study, no significant improvement is achieved in patients received comprehensive treatment based on surgery. It has been reported that surgery was superior to non-surgical treatment mode in second primary SCC after radiation in head and neck region. Systematic treatment in this study is the platinum-based chemotherapy. Given the poor prognosis of second primary OSCC, there is a need to find new treatments to improve the survival.
The use of intensity-modulated radiation therapy (IMRT) for head and neck tumor has been increasing in recent years, as it has the potential to deliver complex dose distributions to avoid critical structures close to the target. However, concerns exist about whether the risk of second cancer after radiotherapy could be reduced. However, Ardenfors et al.[17] investigated whether IMRT and 3-dimensional conformal radiotherapy (3D-CRT) could reduce the risk of second tumors induced by radiotherapy for head and neck tumor. The results showed that the redistribution of the dose characteristic to IMRT only leads to a redistribution of risks in individual tissue, but no difference in total levels of risk was found between the irradiation techniques considered.
The mechanism of the difference between secondary OSCC and sporadic SCC remains unknown. The poor outcome may be attributed to Bmi1 upregulation in the secondary lesions[18]. Patients often present with chronic oral mucosal inflammation after radiotherapy, but it remains unknown whether such inflammation could develop to carcinoma. The mechanism of second primary OSCC requires further investigation.