Clinical Characteristics of Testicular Nonseminomatous Germ Cell Tumor from West China: A 10-Year Experience of a Super regional Center

Obejectives: To evaluate the clinical characteristics and prognostic factors of Nonseminomatous Germ Cell Tumor (NSGCT). Patients and methods: Testicular cancer (TC) survey was conducted by Department of Urology, West China Hospital from 2008 to 2018. Details such as age, tumor size, tumor markers, histopathology, clinical stage, initial treatment, follow up, and clinical outcomes were provided by the database of our center. Tumor stage was classified according to the NCCN criteria(1). Results: Orchiectomy, chemotherapy and radio-therapy were the main treatments for these patients. Clinical stage I, stage II and stage III patients accounted for 74.6% (150), 7.5% (15) and 17.9% (36), respectively. After a median follow up time of 63 months, 4 patients relapsed during observation and 3 of them died. 4 patients died because of advanced malignancies. Among CSI patients, 2 relapsed and 1 died in 3 months after orchiectomy. No recurrence was found in CSII patients. 2 out of 29 stage III cases relapsed after treatment and 3 died of advanced cancer. The 3- and 10- year OS was 95.6% and 88.7%, respectively. For all the patients, the 3- and 10-year PFS was 94.9% and 88.8%. According to our data, we found that the meatastasis and tumor size were risk factors for NSGCTs. Conclusion: The present report showed a good prognosis at non-metastatic stage(CSI). However, the prognosis of advanced disease(CSII and CSIII) is significantly worse than that of early stage. We also found that maximum tumor diameter of >5cm was a potential risk factor for NSGCT.

chemotherapy and radio-therapy were the main treatments for these patients. Clinical stage I, stage II and stage III patients accounted for 74.6% (150), 7.5% (15)  Among CSI patients, 2 relapsed and 1 died in 3 months after orchiectomy. No recurrence was found in CSII patients. 2 out of 29 stage III cases relapsed after treatment and 3 died of advanced cancer. The 3-and 10-year OS was 95.6% and 88.7%, respectively. For all the patients, the 3-and 10-year PFS was 94.9% and 88.8%. According to our data, we found that the meatastasis and tumor size were risk factors for NSGCTs. Conclusion: The present report showed a good prognosis at non-metastatic stage(CSI). However, the prognosis of advanced disease(CSII and CSIII) is significantly worse than that of early stage. We also found that maximum tumor diameter of >5cm was a potential risk factor for NSGCT. Background Testicular tumor represents 1% of male neoplasms and 5% of urogenital tumors. The incidence of testicular cancer (TC) in China is lower than western countries, which is approximately 1 case per 100 000 person-years and showed a slight increase over the past decades. Non-seminomatous germ cell tumors(NSGCT) accounts for nearly 40% of all testicular cancers. Survival of TC including NSGCT has been improving due to advanced multimodal therapeutic options. The majority of NSGCT patients can be cured by orchiectomy and, if necessary, subsequent adjuvant chemotherapy or radiotherapy (2)(3)(4).
Although accurate diagnosis and improved treatment contribute a lot to its good prognosis, there are still some controversies to the treatment of NSGCT for the diverse side effects of those adjuvant therapeutic regimens.
To study the clinical characteristics, treatment and outcome of NSGCT, we have carried out a study of TC adapted by our hospital from 2008 to 2018.

Methods
Information of NSGCT was provided by the database of our center. As this was a retrospective study, ethical approval was not conducted. The inclusion criteria were diagnosis of NSGCT by surgery or needle biopsy. The database included all available details such as age, primary symptoms, laterality, tumor size, imaging examinations(Ultrasound, X-Ray, Computer Tomography ), tumor markers(serum lactate dehydrogenase (LDH), serum β-human chorionic gonadotropin (HCG), serum alpha fetoprotein (AFP)), pathological classification, staging(TNM stage and S stage , clinical stage), initial treatment, time of relapse, and outcome were recorded. Then, according to the criteria of our institution: Normal serum LDH was <220 IU/L, β-HCG <3.81 mIU/ml and AFP <8ng/ml.

Baseline characteristics
Age ranged from 0 to 64 with the mean age of approximately 17 years. Primary symptoms of most patients were simply scrotal masses(187 93.5%), 24(11.9%) presented pain of testis, only 5(2.5%) patient presented respiratory symptoms for lung metastasis( Table 1).

Treatments
As the first-line treatment for seminoma, orchiectomy was performed in 181 patients, 37(20.4%) of these patients received retroperitoneal lymph node dissection and 20 patients received simply testicular tumor dissection. 73 patients (36.3%) received adjuvant chemotherapy after orchiectomy, 1 (T2N0M0 CSIB) received radiotherapy and 8 (4.0%) took both chemotherapy and radiotherapy as the post-surgery therapeutic option.

Prognostic Factors
According to our statistics, for non-metastatic NSGCT(CSI), the 3-and 10-year PFS was 97.7% and 92%, and for metastatic patients(CSII and CSIII), the 3-and 10-year PFS was 85.3% and 77.5%, respectively (Figure 1). Thus showed a significant difference PFS(p=0.003). No relapse or death was found in CSI patients with normal tumor marker, and the 10-year PFS of elevated tumor marker was 86.1%. However, there was no statistical difference between these 2 groups(p=0.226). Comparing PFS between CSI patients who were performed RPLND or not, 2 patients who didn't receive RPLND were observed disease progression after orchiectomy and no progression was found in patients received RPLND. Thus showed a relatively better prognosis for RPLND patients than RPLND-free patients, however, no statistical difference was found between these two groups(p=0.492). Similar result was found between metastatic patients who received RPLND or not(p=0.898). No statistical difference was observed between patients who reveived chemo therapy or not. Taking tumor size into consideration, we found no recurrence or death was found in patients with the maximal tumor diameter of <5cm, however, for those >5cm, the 5-year PFS was 77.9% and showed a notable difference(p=0.003) (Figure 2).

Discussion
The present study is the first large-scale population-based study of the characteristics and survival of NSGCT in China based on registry data of an experienced center. The most common symptoms of NSGCT is simply testicular mass discovered by multiple methods.
And all of our testis samples collected through surgery were identified pathologically.
The first line therapy for NSGCT is orchiectomy. RPLND was not suggested in CSI patients according to the EAU guidelines on TC(2), similarly, RPLND did not contribute to the survival of CSI patients according to the information of our center. We managed to evaluate the difference on survival between CSI patients with normal tumor markers and elevated tumor markers, however, no differences was showed. Further more, no statistical difference was found between patients who was performed chemotherapy versus surveillance. A similar retrospective study was conducted by Ondrusova et al. ,in their study, the relapse rate for surveillance group was 16.7 times higher than that for adjuvant chemotherapy group, so they suggested surveillance was recommended only in patients with low-risk CSI NSGCT. EAU and NCCN guidelines had both recommended surveillance to those CSIA patients and aduvant therapy for CSI patients with primary tumor of pT2-T4 (2,4). For those advanced diseases(CSII and CSIII), no difference in survival was observed in patients who had received RPLND other than orchiectomy and orchiectomy only, there is also no statistical difference in PFS between those who had received chemotherapy and surveillance. However, it was reported by some previous researches and guidelines that RPLND should be performed on CSI patients with conditions against surveillance or chemotherapy, CSIIA patients with or without elevated tumor markers and CSIIB patients with normal tumor markers, chemotherapy should be conducted on all metastatic NSGCT patients (2,4,5). 21 out of 51(41.2%) metastatic patients was lost. Among those patients were followed, chemotherapy was conducted on 23 patients, only 1 patient (T2N0M1bS1 CSIIIC) had received both chemotherapy and radiotherapy. Unlike seminoma, radiotherapy was not suggested in any treatment regimens of NSGCT except for intracranial metastasis (2,4).
However, it was reported recently that the incidence of secondary malignant neoplasms were obviously higher in patients who received chemotherapy than those not (6,7). Other chemotherapy-related multi-system side effects like cardiovascular disease, leukyemia, etc. were also reported by some researchers (8)(9)(10)(11). Every sword has its two sides, advantages and disadvantages of chemotherapy should be evaluated comprehensively.
Considering the high relapse rate of high risk CSI NSGCT(9) and relatively poor prognosis of advanced disease, utilization of chemotherapy is of heavy necessity.
According to the data of our institution, the 3-and 10-year OS was 95.6% and 88.7%, respectively. For all the patients, the 3-and 10-year PFS was 94.9% and 88.8%. For all the patients, the 3-and 10-year OS and PFS rate was 95.6%, 88.7%, 94.9% and 88.8%, respectively According to our statistics, for non-metastatic NSGCT(CSI), the 3-and 10- year PFS was 97.7% and 92%, and for metastatic patients(CSII and CSIII), the 3-and 10- year PFS was 85.3% and 77.5%, respectively(Log Rank p=0.003). markers seemed to show better survival than those elevated, however, no statistical difference was observed between them. Serum LDH is reported to be correlated with tumor burden, growth rate, cellular proliferation, and is commonly higher in patients with advanced disease (16). It was reported that elevated levels of HCG at the time of treatment completion would eventually relapse, while those with normal or lower levels often achieved cure (12,14,17,18) . As for AFP, researchers had found that AFP is elevated in 10-20% CSI seminoma while those with metastatic disease have elevated AFP 40-60% of the time (19). Laterality was not an risk factor according to our data. Primary mediastinal NSGCT (PMNSGCT) and increasing age were reported by other studies as prognosis factors for NSGCT (14).
For the natural shortcomings of retrospective study, one potential drawback of this study is that not all clinical data was collected, such as tumor markers, weight, dose of chemotherapy and radiotherapy etc. However, this could not be avoided. Another limitation of this study is that it spanned over ten years so that 71 patients were unable to follow-up on account of missed telephone numbers or death and other unavoidable reasons.

Conclusions
The present report is the first large-scale study of the clinical characteristics and prognositic factors of NSGCT patients in China based on uni-institutional data.

Ethics approval and consent to participate
The collection and processing of all data were conducted per the Declaration of Helsinki.
After obtaining written informed consent, each patient was evaluated. This study adhered to the Declaration of Helsinki guidelines. Furthermore, as the study include no intervention upon patients, ethical approval was not needed after consulting the the Difference in PFS between metastatic patients and non-metastatic patients.

Figure 2
Difference in PFS between patients with maximum tumor diameter of <5cm and >=5cm.