Malignant fibrous neoplasms of long bones: analysis of the surveillance, epidemiology, and end results database from 1973 to 2015

Malignant fibrous neoplasms (MFN) are very rare malignant tumours of long bones. These tumours include fibrosarcoma, fibromyxosarcoma, periosteal fibrosarcoma and malignant fibrous histiocytoma (MFH) according to classification from the SEER database. Malignant fibrous neoplasms most commonly arise from the extremities [1], occasionally from the nasal cavity and paranasal sinuses [2], and rarely from long bone.

MFH was first described by O’Brien in 1963 [3] and by Kauffman and Stout (Histiocytic tumors (fibrous xanthoma and histiocytoma) in children in 1961 [4]. It was the most common soft tissue sarcoma [5]. Fibrosarcoma of long bone (LBFS) is another neoplasm in this region that exhibits nonspecific symptoms such as pain. The final diagnosis of this tumour is based on histopathology and immunohistochemistry [6].

Malignant tumours of the long bones are challenging with regard to improving patient survival [7]. Few studies have reported the complications associated with surgical resection. Therefore, it remains unresolved whether a uniform treatment strategy could be beneficial to all patients.

Here, we present an epidemiologic analysis of MFN of long bone using the U.S. National Cancer Institute’s SEER database from 1973 to 2015. No previous study has specifically performed an in-depth analysis of cases with MFN of long bones using the database. We analysed 237 cases of MFN of long bones from 18 SEER registries, representing the largest cohort of patients with MFN of long bones studied to date. Our analysis includes demographic and clinicopathologic features of this rare neoplasm, along with its survival outcomes.

Frequency and survival data were obtained from the SEER 18 dataset from 1973 to 2015. SEER had considerably fewer participating registries in the early years, and the number gradually increased relatively recently to reach 18. The cases included in this dataset were diagnosed between 1973 and 2015. Fibrosarcoma cases were screened using the morphological codes for fibrosarcoma (8810/3), fibromyxosarcoma (8811/3), periosteal fibrosarcoma (8812/3), and malignant fibrous histiocytoma (8830/3). Based on the topographical codes, cases with MFN were restricted to the long bone, namely, the long bones of the upper limb, scapula, and associated joints (C40.0), as well as the long bone of the lower limb and associated joints (C40.2).

Frequency data were stratified and analysed by age, gender, race, grade, tumour size, SEER extent of disease, and treatment strategy. SEER extent of disease is categorized into localized, regional, and distant disease. Localized tumour, regional tumour and distant disease are defined as previously reported [8‐11]. Five-year survival rates were calculated using Kaplan-Meier analysis, calculating overall survival (OS) and calculating disease-specific survival (CSS) rates [12]. SEER*Stat 8.1.5 software (National Cancer Institute, Bethesda, MD) and Microsoft Excel 2013 (Microsoft Corp., Redmond, WA) were used to process the data. Statistical Product and Service Solutions (SPSS) 24th edition was used to yield Kaplan-Meier curves and CSS rates. Probability values (p values) < 0.05 were considered statistically significant for all tests.

The demographic characteristics of the 237 patients with MFN of the long bones identified in the SEER database are displayed in Table 1. The specific histopathological diagnosis was fibrosarcoma (21.5%), fibromyxosarcoma (1.7%), periosteal fibrosarcoma (5.1%), and malignant fibrous histiocytoma (71.7%).

Histologically, 55.3% of cases were high grade, 12.2% were low grade, and 32.5% were an unknown tumour grade. More than half (50.2%) of the tumours were at less than 5 cm in size. The extent of disease showed that the majority presented with locally invasive disease (38.4%). Forty-six patients (19.4%) had developed metastasis at presentation. Most patients were diagnosed first with malignant primary tumours (87.8%). After diagnosis, 75.9% of patients underwent surgical treatment and 56.5% of the patients underwent chemotherapy. A total of 160 patients (67.5%) died. The OS rates of the entire cohort at 5 and 10 years were 39.7 and 22.8%, respectively. The CSS rates at 5 and 10 years were 60.3 and 56.5%, respectively.

The 5- and 10-year OS rates for patients with fibrosarcoma of long bones were 31.4 and 11.8%, respectively, and the respective 5- and 10-year CSS rates were 62.7 and 58.8%. For patients with malignant fibrous histiocytoma of long bones, the OS rates were 40.6 and 23.5% and the CSS rates were 58.8 and 55.3%, respectively (Table 1).

Univariate and multivariate analysis of parameters that influence overall survival (OS) and cancer-specific survival (CSS) are illustrated in Tables 2 and 3.

For both OS and CSS, race, gender, decade of diagnosis and tumour type showed no significant effect on survival (p > 0.05; Tables 2 and 3). Univariate survival analysis revealed that older age (age > 60 years) was significantly associated with a worse OS (HR = 7.381, p = 0.001; Table 2; Fig. 1a) and CSS (HR = 3.569, p = 0.032; Table 3; Fig. 2a). Tumour size (> 10 cm) was significantly associated with a worse OS (HR = 4.714, p < 0.001; Table 2; Fig. 1e) and CSS (HR = 7.595, p < 0.001; Table 3; Fig. 2e). Tumour sequence (second) was significantly associated with a worse OS (HR = 1.618, p = 0.031; Table 2) but a higher CSS (HR = 0.042, p = 0.023; Table 3). The stage (distant) was significantly associated with a worse OS (HR = 5.383, p < 0.001; Table 2; Fig. 1f) and CSS (HR = 5.383, p < 0.001; Table 3; Fig. 2f). Radiotherapy was significantly associated with a worse OS (HR = 1.684, p = 0.003; Table 2; Fig. 1d) and CSS (HR = 1.652, p = 0.02; Table 3; Fig. 2d). Surgery was significantly associated with a better OS (HR = 0.267, p < 0.001; Table 2; Fig. 1b) and CSS ((HR = 0.267, p = 0.226; Table 3; Fig. 2b). Chemotherapy was significantly associated with a better OS (HR = 0.688, p = 0.023; Table 2; Fig. 1c) but not with CSS (HR = 0.226, p < 0.001; Table 3; Fig. 2c).

Upon multivariate analysis of all patients (Table 2), age (> 60 years vs < 16 years, HR = 5.688; p = 0.004; 40–60 years vs < 16 years, HR = 3.81; p = 0.027), stage (distant vs. localized, HR = 3.917, p < 0.001), tumour size (> 10 cm vs < 5 cm, HR = 4.051; p = 0.001; 5–10 cm vs < 5 cm, HR = 2.335; p = 0.034), and surgery (HR = 0.397; p < 0.001) were independent predictors of OS.

The results of the multivariate analysis of the parameters that influence CSS are presented in Table 3. Age (> 60 years vs < 16 years, HR = 3.863; 95% CI, 1.14–13.091; p = 0.03), stage (distant vs. localized, HR = 4.401, 95% CI, 2.47–7.841, p < 0.001), tumour size (> 10 cm vs < 5 cm, HR = 3.075; 95% CI, 1.092–8.659; p = 0.033; 5–10 cm vs < 5 cm, HR = 2.335; 95% CI, 1.065–5.124; p = 0.034), and surgery (HR = 0.318; 95% CI, 0.191–0.527; p < 0.001) were independent predictors of CSS.

MFN are rare malignant tumours. Attention was paid to fibrosarcoma, fibromyxosarcoma, periosteal fibrosarcoma and malignant fibrous histiocytoma.

These tumours can infiltrate adjacent tissues and metastasize distally [13‐19]. However, the outcome and prognosis of patients with MFN of long bones have not been reported because of its rarity. To our knowledge, the current study is the first to report the prognostic factors that affect the survival of patients with MFN of long bones using multivariate regression analysis.

In the current study, we identified 237 cases of malignant fibrous neoplasms of long bone based on the SEER database from 1973 to 2015. The OS and CSS rates at 5 years were 39.7 and 60.3%, respectively, while the previous study results showed that the OS and CSS of sinonasal fibrosarcoma were 71.7 and 77.8%, respectively [13].

Although malignant fibrous histiocytoma (MFH) ceased to be recognised as an entity in the 2013 edition of the WHO classification of bone and soft tissue tumours [20], undifferentiated high-grade pleomorphic sarcoma is listed as a new synonym for MFH of bone, still with the same code 8830/3, in the recently published ICD-O-3.2. However, the registrations of undifferentiated high-grade pleomorphic sarcoma of bone still decreased in the seer database. This might explain the recent decrease in registrations of MFH. Therefore, this study was of more than purely historical interest.

This is the largest population-based study to show demographics and analyse the prognosis of patients with MFN of the long bones. Independent predictors of OS included age, stage, tumour size and surgery. Age, stage, tumour size and surgery were also independent predictors of CSS. The results of this study may improve doctors’ understanding of the features and outcomes of MFN of the long bones. It may also be useful for patient health education and to provide a foundation for future research.