Epidemiological profile of soft tissue sarcomas of the extremities: Incidence, histological subtypes, and primary sites

Abstract

Background

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumours that represent less than 1% of all malignant, solid tumours in adults. There is limited epidemiological information regarding STS in Latin America. Therefore, the objective of this study is to present an epidemiological profile of these tumours observed at a single reference centre.

Methods

A retrospective study was carried out based on hospital records obtained from a registry of 879 patients with STS of the extremities who were treated at the National Cancer Institute of Mexico from January 1, 1994 to December 31, 2017. Epidemiological variables and relevant clinical data were collected. Five-year survival rates were analysed using Kaplan-Meier estimates, and a multivariate Cox proportional-hazards model measured associations.

Results

A total of 879 records were collected. The median age was 45 years (15–95 years), and the ratio of men to women was 1:1, with 433 men (49.3%), and 446 women (50.7%). The median tumour size was 11.4 cm (2–49 cm). The most prevalent histological variants were liposarcomas and synovial sarcomas. The lower limb was the most frequently affected extremity, with the thigh being the most common site followed by the leg. A majority of the patients were diagnosed at clinical stages IIIA-IV.

Conclusions

The data collected from the present cohort provides an overview of the epidemiological profile of STS at a single reference centre in Latin America, and allow comparison with global data.

Highlights

• •Soft tissue sarcomas (STS) represent a heterogeneous group of mesenchymal tumours.
• •The main prognostic factors of STS are grade, size, histology, and clinical stage.
• •Wide variations in STS diagnosis and treatment have been identified around the world.
• •Better multidisciplinary strategies for early detection are needed.

1. Introduction

Soft tissue sarcomas (STS) are a heterogeneous group of rare, malignant tumours exhibiting mesenchymal differentiation. Approximate incidence is 1.8–5 per 100,000 people per year^1,2 and constitute 1–2% of all solid malignant neoplasms. It is estimated that 13,130 new cases will occur in the United States in 2020, with 7,470 cases diagnosed in men and 5,660 in women; deaths are estimated in 5,350 (2,870 men and 2,480 women).¹ The frequency of STS has not been well studied in Mexico. According to information from the Histopathological Report of Neoplasms in Mexico,² 1800 new cases and 276 deaths were reported for this disease in 2003, and no updated information is available. The mean age at presentation is 54. They may appear in any anatomic site but affect the extremities (60%) and the retroperitoneum (15%) more commonly.³ Currently, more than 150 types and subtypes of sarcomas with variable growth, progression, and recurrence patterns have been described, which makes their accurate diagnosis difficult and often delays both correct diagnosis and early patient referral to high-volume centers for assessment and treatment. The clinical manifestations of STS are highly variable. Both asymptomatic or rapidly growing lesions that cause pain, function impairment or bleeding can be found at presentation. Typically, these tumours present at advanced clinical stages. Estimated 5-year relative survival across all stages is 58%, and 5-year overall survival is approximately 50%.^1,3

The rarity of soft tissue sarcomas, combined with a diversity of subtypes, makes them difficult to both study and manage outside of high-volume centers, as it is important to be familiar with the particularities of each subtype to ensure adequate treatment. The management of sarcomas of the extremities requires a multidisciplinary approach. Surgery remains the main treatment, however a multidisciplinary team (MDT) approach facilitates coordination between team members, and is currently recommended by institutions like NCCN, ESMO, ECCO, SPAEN and others. When treated within a MDT approach, diagnostic mistakes can be identified, and treatment is individualized. Participating specialists include radiation therapy, medical oncology, reconstructive surgery, rehabilitation, pathology and radiology. Early referral to a sarcoma center is encouraged, initial treatment by non-oncologists is problematic, since these tumours might be approached as benign lesions and, therefore, surgical planning is unadequate.⁴ Up to 59% of a residual tumour maybe present during a re-excision, which further undermines patient prognosis.^5,6 The main prognostic factors of extremity STS are histologic grade, tumour size, resection margins, histological type, and clinical stage.⁷

The absence of specific symptoms leads to limited diagnoses in early stages. Moreover, in comparison to other cancer types, STS occur more frequently in young adults and adolescents; thus, despite a low incidence rate, years of life lost may often be considerable.^7,8 This has encouraged efforts by a variety of associations and societies aiming to design strategies for early detection of soft tissue sarcomas. The European CanCer Organisation (ECCO) published a list of essential requirements for quality care in STS in adults; the Sarcoma PAtients EuroNet (SPAEN) network also proposed patient-driven recommendations for sarcoma care. The creation of a European Reference Network (ERN) on rare adult cancers (EURACAN) including a domain for adult sarcomas aims to facilitate networking and data sharing.⁹ Barriers regarding quality sarcoma care become more challenging in developing countries, in Latin America there is a lack of information even regarding epidemiology of this disease. Also, most countries do not have a regulated path of inter-institutional referral for this case. The objective of this work is to present the clinical and pathological characteristics and prevalence of STS in the extremities, as well as the survival rates of patients from a single reference centre in Latin America during the period from 1994 to 2017, by presenting our experience we expect to boost collaboration with other centers and colleagues interested in sarcoma care.

2. Methods

A retrospective, analytical study was carried out based on hospital records of adult patients (over 15 years of age) diagnosed with primary STS of the extremities that had been confirmed by histopathological and molecular assays during the period from January 1, 1994 to December 31, 2017. All cases with treatment discontinuation, incomplete follow-up, insufficient information to confirm diagnosis, benign soft tissue tumours, desmoid tumours, and Kaposi's sarcoma were excluded. A retrospective database was compiled from the collected data and included the following variables: age, sex, anatomic location of the lesion, histological type, tumour grade according to the French Federation of Cancer Centers Sarcoma Group, clinical stage based on the American Joint Committee on Cancer staging system (AJCC),¹⁰ and treatment.

Patients were assessed by a multidisciplinary team of surgical, radiation, medical and orthopaedic oncologists, plastic and reconstructive surgeons, and radiologists. They determined definitive diagnoses, and clinical and therapeutic stages following local and international reference guidelines.

Overall survival was determined as the time from diagnosis to death or last evaluation. The disease-free period was defined as the time from last treatment to clinical recurrence, and/or by a documented image of a histopathological test, or final note in the medical record indicating no evidence of tumour activity expressed in months. Recurrence was considered as the onset of disease after a 6-month period of absence demonstrated by imaging and clinical assessment. Cases were grouped by age to identify high-risk groups and contrasted by histological type.

2.1. Statistical analysis

Analysis of the data was performed using SPSS ver. 25 (IBM Corp., Armonk, NY, USA). Means, medians and ranges or standard deviations were measured according to distributions. The Kolmogorov-Smirnov test was used to assess normality. The Kaplan-Meier survival estimator was used to determine 5-year survival rates, and a multivariate Cox proportional-hazards model measured association.

3. Results

A total of 879 cases that met the study criteria were included for analysis. The median age of patients was 45 years (range, 15–95 years). The ratio of men to women was 1:1, with 433 cases diagnosed in men (49.3%) and 446 in women (50.7%). The median tumour size was 11.4 cm (2–49 cm). Most cases were diagnosed in locally advanced and metastatic stages. Tumour characteristics are presented in Table 1.

Table 1.

Characteristics of soft tissue sarcomas of the extremities.

Characteristic	N	%
Sex
Male	433	49.3
Female	446	50.7
Ta
Txf	8	0.9
T1	154	17.5
T2	308	35
T3	180	20.5
T4	230	26.2
Nb
N0	832	94.7
N1	47	5.3
Mc
M0	670	76.3
M1	208	23.7
Graded
I	91	10.4
II	139	15.8
III	649	73.9
Clinical Stagee
IA	15	1.7
IB	68	7.7
II	116	13.2
IIIA	218	24.8
IIIB	235	26.7
IV	228	25.9

^aPrimary Tumor.

^bRegional Lymph Node.

^cDistant Metastasis.

^dGrades are based on the Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) group.

^eClinical stage is based on the American Joint Committee on Cancer staging system.

^fTumor cannot be assessed.

The anatomic distribution of STS in our cohort is illustrated in Fig. 1, Fig. 2, and shows more cases occurring in the lower extremities, particularly in the thigh, followed by the leg. The most frequently affected site in the upper extremity was the forearm.

Fig. 1.

Anatomical distribution of soft tissue sarcomas in the upper extremities *Percentages refer to the proportion of total cases.

Fig. 2.

Anatomical distribution of soft tissue sarcomas in the lower extremities *Percentages refer to the proportion of total cases.

The most prevalent histological variants were liposarcomas (25.6%) and synovial sarcomas (25.6%) followed by undifferentiated pleomorphic sarcomas (13%). Synovial sarcomas were more frequent in men, and epithelioid sarcomas were more frequent in women (Table 2). As expected, 5-year OS was associated with histologic type, it was 91% for dermatofibrosarcoma and 22% for alveolar soft part sarcoma. The OS for each sarcoma type is detailed in Table 2.

Table 2.

Histological types and percent 5-year survival of patients with soft tissue sarcomas.

Histological type	N (Total)	%	Males (n)	Females (n)	5-year survival (%)
Liposarcoma	225	25.6	115	110	77.3
Synovial sarcoma	225	25.6	122	103	55.4
UPSa	114	13.0	54	60	68.5
MPNSTb	41	4.7	23	18	52.5
Leiomyosarcoma	36	4.1	14	22	69.4
Extraosseous Ewing Sarcoma	30	3.4	7	23	30
Epithelioid sarcoma	26	3.0	8	18	57.7
Fibrosarcoma	22	2.5	11	11	68.2
Rhabdomyosarcoma	22	2.5	14	8	54.5
Sarcoma not classifiable	20	2.3	6	14	50
Dermatofibrosarcoma	15	1.7	5	10	91
Cutaneous angiosarcoma	13	1.5	7	6	38.5
Low-grade myofibroblastic sarcoma	11	1.3	7	4	72.7
Alveolar soft part sarcoma	9	1.0	7	2	22.2
Clear-cell sarcoma	6	0.7	3	3	33.3
Others	64	7.3	31	33	71.9

^aUPS: undifferentiated pleomorphic sarcoma.

^bMPNST: malignant peripheral nerve sheath tumour.

The distribution of each STS by age group is presented in Table 3, and most common sarcoma types are highlighted. We found that younger patients had a high proportion of aggressive tumours such as synovial sarcoma and extraosseous Ewing sarcoma. Clinical stage was also an important prognostic factor. The differences in 5-year survival for each stage is shown in Fig. 3.

Table 3.

Number of patients with soft tissue sarcomas of the extremities by age distribution.

Histological type	Age at diagnosis
	15–29	30–39	40–49	50–59	60–69	70–79	80+	Total
Liposarcoma	22	46	44	51	42	16	4	225
Synovial sarcoma	106	49	33	20	12	5	0	225
UPSa	7	3	20	23	31	16	14	114
MPNSTb	11	10	6	10	0	3	1	41
Leiomyosarcoma	6	2	9	7	8	4	0	36
Extraosseous Ewing Sarcoma	19	5	2	4	0	0	0	30
Epithelioid sarcoma	8	5	4	2	6	1	0	26
Fibrosarcoma	7	2	3	2	4	3	1	22
Rhabdomyosarcoma	11	3	3	3	2	0	0	22
Sarcoma not classifiable	1	0	3	6	8	2	0	20
Dermatofibrosarcoma	2	1	2	5	4	1	0	15
Cutaneous angiosarcoma	4	1	2	2	1	3	0	13
Low grade myofibroblastic sarcoma	0	1	1	4	0	1	4	11
Alveolar soft part sarcoma	8	1	0	0	0	0	0	9
Clear cell sarcoma	3	2	0	0	1	0	0	6
Other	5	6	14	9	13	10	7	64

^aUPS: undifferentiated pleomorphic sarcoma.

^bMPNST: malignant peripheral nerve sheath tumour.

Fig. 3.

Overall 5-year survival by clinical stage (AJCC 8a ed sarcomas of the extremities and trunk).

4. Discussion

This study is the largest case series of extremity soft tissue sarcoma from a single referral center in Latin America. The most recent Latin-American study regarding the epidemiological profile of sarcoma patients was published by the Instituto de Enfermedades Neoplásicas del Perú (INEN). The authors reported a retrospective cohort of 250 cases; unlike in our cohort they found a higher incidence of STS in males (60.8%), and the histologic types were also different, most of their cases were UPS and LPS.¹¹ Our series is quite larger, and so the findings are expected to be different. In another study published by Corey et al. from the United States of America.,¹² the authors found the most frequent histological types to be liposarcoma followed by malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma). Burningham et al. Summarizing the results of various centers in the United States and Europe present a higher incidence of fibrosarcoma, followed by malignant tumours of the peripheral nerve sheath, which differs considerably from what was presented in our series.⁷ Another study from the database of The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER), the predominant histology was Leiomyosarcoma, followed by undifferentiated pleomorphic sarcoma and liposarcoma, which shows a great heterogeneity of results and allows visualizing differences in different regions geographical.¹⁷ As we reported in a previous publication, there is a higher incidence of synovial sarcomas in our population in comparison to other published reports.^6,13, 14, 15, 16, 17 This might be related to a worse OS in this cohort (5-years OS 39%). Further investigation has, shown that the elevated incidence of synovial sarcomas is not associated with racial, occupational, or genetic risk factors, which is in agreement with other studies.^6,16, 17, 18, 19 The data presented is valuable because it not only allows a better understanding of the heterogeneity of the disease, it can also be used by researchers around the world to select countries where they'd be more likely to recruit patients with specific STS types (such as Synovial Sarcoma).

Systemic treatments given in a neoadjuvant or adjuvant therapy in selected high-risk STS is still a topic of debate, given the low incidence of this disease, data from multicentric trials is needed; however Latin American countries are not included in this trials. From a sample of 10 multicentric clinical trials studying systemic treatment for STS, (NCT01710176, NCT00002791, NCT00346164, NCT01696669, NCT00002641, NCT00304083, NCT03526679, NCT04145700, NCT02359474) Only 1 included a Latin-American Country. Given our specific epidemiological profile, it should be expected that these countries would be included in clinical trials, and it is not the case.

There is a discrepancy between the incidence of some subtypes of sarcomas between the US, Latin America and in our series, as described previously. This might be due to newer and better diagnostic techniques, both immunohistochemical and molecular which have generated a change in classification and staging; so it is important to maintain updated information in this disease. Specific risk factors for the development of sarcomas and their relationship with the geographical variation in sarcoma types is poorly understood, so further epidemiological global information is important in understanding this disease. Variations seemingly as simple as country of origin explain discrepancies in oncological outcomes, and even more advanced disease stages do not account for all poorer outcomes in LMIC, this has been reported for other malignancies; the rarity of sarcomas might even accentuate this effect.

An important challenge for cancer registries will be to develop the ability to track, at the population level, the highly selective improvements resulting from this kind of ‘histology-driven’ or ‘molecularly driven’ therapy, affecting single histologies or clinical presentations with low numbers of eligible patients. A proper pathologic diagnosis on a population basis would be crucial in this regard, and it is well known that this is still a challenge.

In our study, the age at which STS first presented was similar to what was reported by the INEN group,¹¹ although it is 10 years younger than the average age in a French population, as reported by Honoré et al.²⁰ Unlike other papers, our cohort had a higher proportion of extremity STS in patients younger than 50 years. This is in contrast to other studies such as Amankwah et al.¹⁶ who reported an elevated incidence in patients older than 65 and Bhatt²¹ who found a higher incidence in patients over 60 years using an Irish database. These results may be explained by the main histological types, which differed between these cohorts. Younger patients often have better performance status, which is an important inclusion criteria in clinical trials.

Although the ability to perform limb-saving surgery has improved and general knowledge has advanced, overall survival has not increased. Risk stratification based on prognostic criteria, surgical techniques, perioperative management, and adjuvant therapy has been suggested to have reached the current limits of efficacy for soft tissue sarcomas of the extremities.^10,11,22 The clinical stages in our cases were predominantly locally advanced stages, IIA (51.5%) and IIIB (25.9%) In our cohort, 5y-OS was only 39%, which may have been due to the advanced clinical stages of the disease and histologic types seen in our cohort.

There are several limitations to our study. First, this was a retrospective cohort. In addition to this, changes in histological classifications, such as malignant fibrous histiocytoma, can affect incidence and survival rates. It is difficult to compare tumours formerly known as malignant fibrous histiocytoma with the current category of high-grade pleomorphic sarcoma, and with more histological subtypes and variable treatment modalities, they could reveal subtle differences in survival. However, it would be beyond the scope of a single article to examine the statistical nuances of each type of sarcoma. To increase the validity of this study, all histological diagnoses were confirmed by two sarcoma pathologists, which provided greater diagnostic certainty. Second, this was a single center study. These limitations highlight the need for more epidemiological data that allows us to understand the natural history and biological behaviour of sarcomas throughout the population. It is also a call to the scientific community around the world for the development of mega databases that allow the design of more robust clinical studies and that allow us to verify the efficacy of new diagnostic methods and new therapeutic modalities and with this improve oncological results in sarcoma patients.

5. Conclusions

This study provides an overview of the epidemiological profile of STS from a reference centre in Latin America. We expect that our presentation of the epidemiological characteristics found in our population can be used to improve treatment strategies based on the incidence of the disease, ranging from timely diagnostic approaches, early referrals, personalized treatments and translational research. Our results also indicate that, although classified as a rare disease, STS occur in an economically active sector of the population in comparison to other malignant neoplasms.

Ethics approval

This research study was conducted retrospectively from data obtained for clinical purposes. An IRB official waiver of ethical approval was granted from the IRB of NCI (Mexico).

Funding

Not applicable.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Credit author statement

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Dorian Y Garcia-Ortega], [Leonardo S Lino-Silva], [Rosa A Salcedo-Hernandez] and [Cuauhtémoc de la Cruz Ruvalcaba-González]. The first draft of the manuscript was written by [Dorian Y Garcia-Ortega] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript

Declaration of competing interest

The authors declare that they have no conflict of interest.