Malignant Fibrous Histiocytoma: Database Review Suggests a Favorable Prognosis in the Head and Neck

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2 The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. Malignant Fibrous Histiocytoma: Database Review Suggests a Favorable Prognosis in the Head and Neck Robert B. Borucki, BS ; David M. Neskey, MD; Eric J. Lentsch, MD Objective: The malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma of the head and neck. Currently, most of the data on this tumor relies on small retrospective studies. The objective of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to compare characteristics of this tumor based on location to better understand its prognosis in the head and neck region. This article represents the largest study analyzing prognosis of this tumor in the head and neck to date. Study Design: Retrospective analysis of SEER database. Methods: Using the SEER database, 395 patients with MFH of the head and neck were compared with 3,968 patients with MFH of the trunk and extremities. Disease-specific survival was carried out comparing these two cohorts, as well as univariate and multivariate analysis to determine hazard ratios. Results: Head and neck MFH had a significantly higher disease-specific survival compared with trunk and extremity disease. However, head and neck tumors were more frequently a smaller size (P<.0001) and lower grade (P<.0001). Larger tumors and grade III and IV tumors conferred a worse prognosis (P<.0001). Conclusion: Head and neck malignant fibrous histiocytoma presents at a smaller size and lower grade, likely due to earlier presentation in this region. Because of this, head and neck malignant fibrous histiocytoma represents a more favorable survival prognosis compared with trunk and extremity disease. Key Words: Malignant fibrous histiocytoma, sarcoma, head and neck, SEER, survival. Level of Evidence: 4. Laryngoscope, 128: , 2018 INTRODUCTION Sarcomas make up between 1% and 2% of tumors of the head and neck, which is a small but significant group of malignancies. 1 The malignant fibrous histiocytoma (MFH) is a sarcoma first described by O Brien and Stout in 1964 and is the most common soft tissue sarcoma of the head and neck. 2 5 It is a moderately aggressive sarcoma capable of invading soft tissue and skeletal structures. 6 This tumor has historically demonstrated aggressive behavior in the head and neck region with poor survival. 7 Some studies have found that MFH had a significantly decreased overall survival in the head and neck region compared to the rest of the body. This may be due to its presentation near vital structures and subsequent difficulty with surgical excision. 8 The larynx, maxillary sinus, and mandible have the worst prognosis in this region, with death often due to advanced local disease rather than distant metastasis Due to the rarity of this tumor, most of the data on its prevalence and treatment outcomes From the College of Medicine (R.B.B.); and the Department of Otolaryngology Head and Neck Surgery (D.M.N., E.J.L.), Medical University of South Carolina, Charleston, South Carolina, U.S.A. Editor s Note: This Manuscript was accepted for publication August 16, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Robert B. Borucki, BS, College of Medicine, Medical University of South Carolina, Charleston, SC boruckir@musc.edu DOI: /lary are based on small retrospective studies or management of similar sarcomas. By utilizing the Surveillance, Epidemiology, and End Results (SEER) database, this article draws conclusions from the largest cohort of head and neck MFHs currently available. The largest previous study looking at MFH in the SEER database analyzed these tumors in the broader context of head and neck sarcomas. 12 The goal of this study is to use the SEER database to compare characteristics of MFH based on location, with the purpose of better understanding prognosis and ultimately guiding treatment of this disease in the head and neck region. MATERIALS AND METHODS Data Source The SEER program database was accessed to gather frequency and survival data. This database is a collection of cancer registries across the United States that covers about 28% of the total population. Specifically, The SEER 18 dataset was used, which covers 18 registries between the years of 1973 and This project was exempt from the institutional review board review process because patient information was de-identified prior to usage. Patient Selection This study included patients diagnosed with MFH between the years of 1973 and This tumor was isolated using the SEER variable Histologic Type ICD-O-3 (International Classification of Diseases for Oncology-3) and the specific code 8830/3 for fibrous 885

3 TABLE I. Demographics and Clinicopathologic Characteristics of MFH Patients. Head and Neck Trunk and Extremities n % n % P Value Total 395 3,968 Median age at diagnosis, years Age <.0001 < , Gender <.0001 Male , Female , Race <.001 White , Black Other Size <.0001 < 5 cm cm , Unknown* Histologic grade <.0001 I II III , IV , *Size variable not recorded for 748 patients. P values in boldface indicate statistically significant difference. MFH 5 malignant fibrous histiocytoma. histiocytoma, malignant. The location groupings of head and neck and trunk and extremity tumors were created using data from the SEER ICD-O-3 site recode variable. Any tumors in patients under 18 years of age and tumors involving the central nervous system were excluded. Patients with an unknown pathologic grade, unknown survival time, and those whose tumor was not their primary were excluded from analysis. Patient Stratification After careful selection of the appropriate patient population; information on the patient s sex, race, age at diagnosis; histologic grade; and tumor size was gathered. Respectively, the following SEER variables were used: sex, race recode, age recode with single ages and 851, grade, CS tumor size, EOD 10 size, and EOD 4 size. The age at diagnosis variable was broken down for analysis into patients younger and equal to or older than 50 years of age. This age was chosen to provide a point of comparison between younger and older patients. Similarly, tumor size was differentiated into two groups: smaller than and equal to or greater than 5 centimeters in diameter. Demographics Patients diagnosed with MFH were separated into two categories based on location of the tumor. One group contained tumors of the head and neck, whereas the other group consisted of tumors of the trunk and extremities. The differences in demographics and clinical features of these tumors are shown in Table I. The statistical significance of these differences was calculated using Fisher s exact test and chi-square when appropriate. Survival Analysis Disease-specific survival was calculated using the SEER data on survival months and cause of death. This data was gathered from the SEER variables survival months and SEER cause-specific death classification, respectively. Kaplan- Meier estimates were used to analyze this data, and log-rank tests were used to determine statistical significance. Univariate and multivariate analysis were carried out using the Cox regression model, and hazard ratios (HRs) were obtained. The multivariate Cox proportional hazard regression included the confounding variables of tumor size and grade. Statistical Analysis The information gathered from the SEER database was analyzed using SPSS 24.0 (IBM Corp., Armonk, NY). The cutoff P value of 0.05 was used to indicate statistical significance for all analyses. RESULTS Demographics A total of 4,363 patients with this tumor who fit the specified inclusion criteria were identified. This group was further broken down into the 395 patients diagnosed with MFH in the head and neck region and 3,

4 (HR , 95% confidence interval [CI], , P <.0001). When controlling for tumor size and grade, the multivariate analysis showed a weaker HR, although still with statistical significance (HR , 95% CI, , P <.01). Fig. 1. Kaplan-Meier estimate of MFH disease-specific survival by regional cohort. DSS 5 disease-specific survival; MFH 5 malignant fibrous histiocytoma. patients with a tumor in the trunk or extremities. Compared to the total frequency of MFH, 9.1% occurred in head and neck region, whereas 90.9% occurred in the trunk and extremities. The demographics and characteristics of this tumor are compared by location in Table I. The median age of diagnosis in head and neck patients was 73 (mode 5 78) years and in trunk and extremity patients was 64 (mode 5 73) years. The upper limit of age in years in the SEER database is 851; therefore, mean age could not be calculated. The frequencies of each MFH cohort differentiated by tumor grade also are shown in Table I. There was not much separation in tumor grades II, III, and IV within the head and neck cohort; each of these grades occupied approximately 30% of tumors. However, grade IV tumors occurred more frequently than other grades in the trunk and extremities cohort at 47% (P<.0001). DISCUSSION The rarity of MFH and sarcomas in general make the characterization and analysis of these tumors particularly difficult. Although many articles in the past have focused on differentiation of the MFH from other sarcomas on a molecular level, few have looked at patient outcomes, specifically in the head and neck region. Clark et al. (2011) report this tumor in the head and neck to be aggressive with a poor prognosis. 7 Sabesan et al. (2006) carried out a study similar to this one, using retrospective data to compare this tumor in the head and neck to the rest of the body. Based on their institutionwide review, they found that head and neck tumors portend a significantly worse overall survival compared to tumors of the trunk and extremities. 8 Our study contradicts these findings, likely because we sought patients differently and used disease-specific survival, suggesting that tumors of the head and neck have a significantly better prognosis. The use of diseasespecific survival in this case is likely to give us a more accurate depiction of the MFH disease process. The larger sample size provided by the SEER database also strengthens this evidence in support of a better prognosis in the head and neck. Peng et al. (2014) carried out a similar SEER database study, which showed similar results for MFH survival. This study focused on several head and neck sarcomas rather than solely MFH and did not compare tumors by body region. The current study looks specifically at MFH and focuses on a comparison between body regions rather than the type of sarcoma. The variation in specific numbers obtained from the SEER database is likely due to the year the database was accessed, as well as differing inclusion criteria for the studies. 12 The major factor that helps explain the improved prognosis of head and neck tumors is the characterization of the tumor at presentation. Table I shows that only Survival Analysis The comparison of disease-specific survival between the head and neck cohort and the trunk and extremities cohort is shown in Figure 1. The head and neck cohort showed a statistically significant increased survival (P <.0005). The 2-, 5-, and 10-year survival rates for head and neck tumors were 86%, 78%, and 73%, respectively. For the trunk and extremity tumors, the 2-, 5-, and 10-year survival rates were 74%, 63%, and 58%, respectively. Univariate and multivariate analyses were performed to determine the HRs associated with head and neck compared to trunk and extremity tumors. These results are shown in Table II. The multivariate analysis included the tumor size and grade. The univariate analysis showed an increased risk of death with trunk and extremity tumors TABLE II. Comparison of Univariate and Multivariate Analysis by Region in Disease-Specific Survival of MFH. Analysis Univariate Hazard Ratio (95% CI) P Value Head and neck 1 Reference Trunk and extremity 1.91 (1.52, 2.39) <.0001 Multivariate Head and neck 1 Reference Trunk and extremity 1.38 (1.10, 1.75) <.01 P values in boldface indicate statistically significant difference. Multivariate signifies the inclusion of tumor grade and size in the analysis. CI 5 confidence interval; MFH 5 malignant fibrous histiocytoma. 887

5 20.8% of head and neck tumors were larger than 5 centimeters, whereas 59.9% of trunk and extremity tumors were this size (P<.0001). In addition, 29.9% of head and neck tumors were grade IV, whereas 47% of trunk and extremity tumors were this same grade. This data suggests that the head and neck tumors at presentation are smaller and less aggressive than trunk and extremity tumors. Based on the HR obtained through the Cox regression, Table II shows that trunk and extremity tumors carry an increased risk of death. After controlling for tumor size and grade in the multivariate analysis, the increased risk of death for trunk and extremity tumors, although still significant, is not as great. This suggests that the variables of tumor size and grade do play some role in the discrepancy in disease-specific survival between these two regions. This could be due to the cosmetic and functional morbidity associated with a mass in the head and neck region compared to a patient s benign perception of a painless mass in the trunk or extremity. Due to the later presentation in the trunk and extremities, these patients tend to fare worse, leading to a significantly decreased disease-specific survival. Although it is not clear what other factors aid in the improved survival for head and neck tumors, these findings suggest that variations in the tumor size and grade have some influence over the difference in survival by region. Several limitations in the scope and application of this study must be acknowledged. Primarily, this article is limited to the variables and patient population contained within the SEER database. Although this is an extensive population, it is not a complete record of MFH patients. A larger sample size of this relatively rare tumor certainly would be beneficial in understanding its nature and prognosis. The standardization of data to fit the SEER database also makes specific treatment methods and recurrence data difficult to track. Another important variable that was not analyzed in this research is the influence of treatment type on survival. Most MFH patients are treated with surgical excision, along with the option of adjuvant radiation therapy. Based on variations in the SEER procedure coding over the previous decades, it is difficult to accurately compare different surgical procedures. Therefore, treatments were left out of this preliminary study. In addition, patient morbidity and quality of life after surgery were not studied, which is an important factor to consider after wide local excision in the head and neck region. Nevertheless, these data provide novel insight into the prognosis of this disease in different regions of the body. In addition, the results of this study are limited by the reclassification of this tumor over the past few decades. This tumor generally is characterized as a pleomorphic sarcoma with both fibroblastic and histiocytic differentiation; however, the diagnostic criteria have varied due to advancements in cytogenetics and immunohistochemistry. 14 Recent studies have argued that the MFH is not of fibroblastic or histiocytic origin, leading to a reclassification of this tumor as an undifferentiated pleomorphic sarcoma. 15 Current hypotheses suggest that this tumor is a common endpoint in dedifferentiation for several sarcomas, but its exact origin remains unknown. 16 Although the renaming of a collection of histologically similar tumors will not affect the prognosis of the disease, the potential misclassification of older tumors may limit the findings of this study. CONCLUSION Although one of the most common sarcomas of the head and neck, the MFH is a rare tumor that remains a poorly understood entity. 1,3 This study represents the largest retrospective study to date analyzing the characteristics and prognosis of MFH. Analysis of the SEER database shows a significantly higher disease-specific survival of patients with a tumor of the head and neck compared to one of the trunk and extremities. In addition, tumors of the head and neck are disproportionately smaller and lower grade than those in the trunk and extremities. This finding suggests that head and neck tumors are diagnosed earlier in their course, explaining their particularly favorable prognosis. Although these findings are useful in understanding the prognosis of MFH, further large-scale studies are necessary to identify and refine improved and novel treatment options. BIBLIOGRAPHY 1. Kraus DH. Sarcomas of the head and neck. Curr Oncol Rep 2002;4: O Brien JE, Stout AP. 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