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Spindle cell sarcoma: a SEER population-based analysis

Due to the substantial limitation of study population, Spindle cell sarcoma (SCS) was unexplored comprehensively. In this study, we investigated the clinical characteristics and disease specific prognostic factors of SCS. 3299 SCS cases were identified and extracted from Surveillance, Epidemiology, and End Results (SEER) database (1973–2017). White people account for 79.1% with median age of 57 years without predominance in any gender. Significant disease specific survival (DSS) and overall survival (OS) were found differentiated in age, T stage, N stage, M stage, AJCC stage, SEER historic stage, tumor locations, surgery, and pathologic grade. In the multivariate Cox analysis, the age >64 years (for DSS, P < 0.001 and for OS, P < 0.001; Reference age ≤64 years), AJCC stage III (for DSS, P = 0.006 and for OS, P = 0.04; Reference: AJCC stage I), and non-surgical treatment (for DSS, P < 0.001 and for OS, P < 0.001; Reference: surgery) were independently associated with worse DSS and OS. In brief, our study demonstrated that SCS mostly found in white people at fifth to seventh decades of life without gender predilection. The patient’s age, AJCC stage, tumor location and surgery were independent prognostic indicators for both DSS and OS of SCS.

SCS could occur at almost any site of the body. The incidence was higher in superficial primary tumor site than internal primary tumor site (2041 vs. 1151 cases). More than 60% of overall case were treated surgery alone.
Among 3229 cases, 2115 cases were found with SCS specific mortality, in which included 1026 female and 1089 male with median age was 57 years (SD = 19). In this disease specific survival (DSS) group, white people account for nearly 80% of population (79.1%, 1674/2115). Regarding the pathological diagnosis, poorly differentiated cases were 27.5% (357/1300) and undifferentiated cases were 42.6% (554/1300). There were 302 early stage cases (AJCC stage I + II) and 367 advanced stage cases (AJCC stage III + IV). The basic clinic-pathological characteristics of overall study population and DSS subgroup summarized in Table 1.
In the univariate cox regression analysis, age, race, pathologic grade, AJCC stage, T stage, N stage, M stage, SEER historic and stage treatment were associated with DSS and OS (  (Table 3).

Discussion
According to current investigation, SCS affects people of almost all ages which was as same as soft tissue sarcomas 21 . SCS occur more commonly in middle and old age adult groups. In this series, SCS most frequently occurs during the seventh decades of life with the mean age at diagnosis of SCS is 61 years. In addition, there is no statistically significant difference on incidence rate in gender. However, there is predominance in male with a sex predilection of 1.11:1 male: female ratio in a previous report 22 . Besides, the overall race distribution includes 80.9% white, 11.4% black, 7.8% American Indian/Asian/Pacific Islander (Table 1). According to the survival analyses depending on demographic factors such as age, gender and race, it demonstrates that only age is an independent prognostic indicator for SCS in DSS and OS. The treatment modalities were performed for SCS varied, including surgery, adjuvant radiotherapy and chemotherapy in previous available reports. In this study, we only concentrate on the obtainable treatment modality (surgery or not) and hopefully to confirm the role of surgery in SCS treatment. Despite of the difference in surgical style, the surgery group have absolute favorable survival in DSS and OS than non-surgery group. Thus, it indicates that surgical resection remains the mainstay of treatment for SCS. However, the value of extensive radical operation and lymphadenectomy is still ambiguous. Similarly, the descriptive results should not be misinterpreted as causal effects of surgery on survival because of the unavoidable severe treatment selection bias present in this retrospective data source. In addition, the use of adjuvant radiotherapy for SCS remains controversial, and the sensitivity of SCS to chemotherapy in the metastatic setting is highly variable 23 . Unfortunately, due to the lack of information on other therapies in this study, we are unable to determine the conclusion from this data that SCS patients cannot benefit from radiotherapy or chemotherapy.
The pathologic grade and TNM/AJCC stage are associated with outcome of sarcomas and it is important for treatment protocol planning [24][25][26] . In this study, although the pathologic grading data in this study was incomplete and half of them were missing in the SEER database, there are still 1986 cases available. According to the SEER Program user's instruction, cases were listed with latest pathological grading system. Although two histological grading systems are mainly used for soft-tissue sarcoma: the National Cancer Institute (NCI) system and the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system, but there is still no specific system can be used for spindle cell sarcoma. So we used the four-tiered grading system which was most commonly used, and recommended by the American Joint Commission on Cancer (National Cancer Institute, "Tumor Grade", accessed 18 August, 2014) 27 . SCS were divided into four different pathologic grades basing on the degree of the cell differentiation 28 . In results, most of the cases are advanced grade at the first time when they are diagnosed, which includes 546 cases at grade III (pathologically poorly differentiated, 27.5%) and 873 cares at grade IV (pathologically undifferentiated, 42.6%). Previous reports demonstrated pathologic grade is a significant The tumor origination is another important factor affecting the outcome of the tumor. SCS can occur in any anatomic location including soft tissue, bone, or viscera 30 . This study included all of the cases listed as spindle cell sarcoma which were pathologically confirmed (International Classification of Diseases for Oncology, Third Edition, Histologic Type ICD-O-3: 8801) including bone origination, meanwhile excluded undifferentiated high-grade pleomorphic sarcoma (8830/3) which is new category recognizes pleomorphic sarcomas that cannot be classified into any of the other categories. Above all, our study is the largest series of patients and intend to evaluate the primary tumor location as a prognostic factor for the first time. As previous studies, SCS occurred at any location of the body involving skin and subcutaneous connective tissue, tongue, sinus, trachea, atrium, vein, bone, etc. 11,31,32 . For better characterization and further evaluating, we categorized the tumor locations into two main groups according to the distribution of primary tumor site: superficial site (tumor involving skin and subcutaneous soft tissue in head & neck, upper limb & shoulder, lower limb & hip, thorax & breast, abdomen, pelvis, trunk and other) and interior site (included tumor involving bone or viscera of digestive system, respiratory system, reproductive system, locomotors system, urinary system, nervous system, endocrine system, circulatory system). In this categorization (Tables 4 and 5), we found that SCS was more likely to occur in the superficial site compare with the deep interior site (2014 superficial site cases versus 1151 interior site cases). And significant survival differences were found in both DSS and OS for SCS (Figs 2J and 3J). More importantly, tumor site is another independent prognostic indicator for SCS in both DSS and OS which means primary SCS locates in superficial site possibly have a better outcome.
The several important limitations that come with this study were acknowledged. Most importantly, the use of other treatment modalities is not recorded in the SEER database. Thus we could not identify the role of other treatment modalities, like radiotherapy or chemotherapy, in treatment for SCS. Besides, there are lack of information neither about surgery type nor resection margin status of the tumor. Similarly, it should be noted that some other important data specifically relevant to the tumor including TNM stage, AJCC stage, margin status, local or distant recurrence, lymphatic metastasis status, are either incomplete or absent. Additionally, we have to point  out that the follow-up time in SEER is not even and long enough. However, this study is the first using such a large and comprehensive representative registry database to demonstrate the demographic features, clinic-pathologic characteristics, prognostic factors of spindle cell sarcoma.
In summary, it is definitely the largest data about SCS which came from SEER database. Despite its preliminary character, this study can clearly indicate the information on demographic features, distinctive clinicopathologic characteristics, tumor specific prognostic factors and treatment outcome by performing comprehensive analysis of the 3299 SCS cases from the database. The study does demonstrate that SCS mostly occurred during fifth to seventh decade of life in white people without gender specific. More importantly, we found that the ageå 64 years (

Materials and Methods
The data extraction and statistical analysis were performed as described previously 19,20 . In brief, the data were extracted with International Classification of Diseases for Oncology codes 8801/3 for SCS from 1973 to 2017 by using official software SEER*Stat, version 8.3.4. Overall statistical analysis was performed by utilizing the software of the Statistical Package for Social Sciences, version 23.0, for Windows (SPSS, Chicago, IL) and survival tabs were generated by GraphPad Prism, version 5.01. The survival curves were generated by using the Kaplan-Meier method, and the survival difference was evaluated by performing the log-rank test. Adjusted hazard ratios (HRs) along with 95% confidence intervals (CIs) were calculated by using the Cox proportional hazards regression model. Differences in the numerical variables were assessed using the Student's test or non-parametric Wilcoxon test. Categorical variables comparisons were evaluated by the chi square test or Fisher exact test. When the P value was <0.05, the difference was regarded as statistically significant. All statistical tests were two tailed.
Ethical approval. This article does not contain any studies with human participants or animals performed by any of the authors.