Abstract
Background/Aim: Distant metastasis has a strong influence on prognosis in patients with soft tissue sarcoma (STS). While various risk factors have been reported for distant metastases, risk factors for distant metastases early after treatment of primary tumor have not been investigated. This study aimed to evaluate the factors of early distant metastasis after primary tumor resection in patients with STS. Patients and Methods: We retrospectively identified patients with STS involving the extremities or trunk without any metastasis at the first visit. Data on clinical information and detailed assessment were collected. We evaluated clinical information as a risk factor for distant or lung metastases. Additionally, we evaluated risk factors for metastases in patients with distant metastases as early as 6 months after the initial resection of the primary tumor. Results: A total of 337 patients were included in the study. Multivariate analysis revealed that the size of the primary tumor (p=0.0011 and p=0.0167), consultation in a short period after onset (p=0.0325 and p=0.0402), histological high grade (p=0.0006 and p=0.0002), and inadequate surgical margin (p=0.0151 and p=0.0055) were significant predictors for poor prognosis for all distant and lung metastases, respectively. However, the only risk factor for early metastases within 6 months was young age (p=0.0148). Conclusion: The only risk factor for early distant metastasis after primary tumor resection in patients with STS was young age, even though large tumor diameter and histological high grade were risk factors for distant metastasis.
Soft tissue sarcoma (STS) is a relatively rare malignant tumor of the extremities and trunk, occurring predominantly in middle-aged and older adults. Various studies have identified factors that are associated with prognosis of patients with STS (1-11). Particularly, distant metastasis, primarily involving the lungs, has a strong effect on the prognosis of patients with STS. Recent developments in surgical treatment, radiotherapy, and chemotherapy have improved patient outcomes. However, distant metastases still appear frequently after excision of the primary tumor. In such cases, it is predicted that the prognosis will be worse if distant metastasis appears earlier. While various risk factors have been reported for distant metastases that significantly affect the prognosis of soft tissue sarcoma (12-17), risk factors for the appearance of distant metastases early after treatment of the primary tumor have not been investigated.
Therefore, the present study aimed to examine the factors of early distant metastasis after primary tumor resection in patients with STS.
Patients and Methods
Patients. We retrospectively identified patients with STS involving the extremities or trunk, without any metastasis at the first visit, treated at our two hospitals between 1994 and 2021. Patients’ records were searched to collect data including age, sex, histological subtype and malignancy, anatomical tumor location, size, period from onset to consultation, presence or absence of unplanned excision, primary tumor treatment, lung and other metastasis, local recurrence, follow-up period, and outcomes. The specimens of soft tissue sarcoma were classified using the French Federation of Cancer Center Sarcoma Group system (FNCLCC), which includes the mitotic index, necrosis extension, and histological differentiation (15). We additionally collected information on the type of local therapy and surgical margins (Enneking staging system) for patients who underwent surgery (18). In the absence of any events, patients were deidentified at the last follow-up.
We evaluated clinical information as a risk factor for distant or lung metastases in all patients. In addition, we evaluated risk factors for distant or lung metastases in patients with distant metastases as early as 6 months after the initial resection of the primary tumor.
This study was approved by the Institutional Review Board for Clinical Research at the Akita University (Approval Number: 2830) and was conducted in accordance with the 1975 Declaration of Helsinki and its 1983 revision.
Statistical analysis. All continuous variables are expressed as mean±standard deviation. A Cox proportional hazards model was used to identify the factors that were associated with distant or lung metastases, and multivariate logistic regression analysis was used to identify the factors that were associated with all and lung early metastasis. A p-value of <0.05 was used to define statistical significance.
Results
A total of 337 patients (175 males and 162 females) with STS without any metastasis at the first visit were included in this study. The mean age was 62.9 years (range=0-94 years) and the mean follow-up was 58.6±49.5 months (range=1-299 months). The median period from onset to consultation was 17.0±40.5 months (range=0-420 months). Past inappropriate excision was conducted in 48 patients (14.2%). The histological diagnoses of STS were dedifferentiated liposarcoma (n=34), pleomorphic liposarcoma (n=17), myxoid liposarcoma (n=37), myxofibrosarcoma (n=77), undifferentiated pleomorphic sarcoma (UPS) (n=64), synovial sarcoma (n=27), malignant peripheral nerve sheath tumor (MPNST) (n=26), leiomyosarcoma (n=25), epithelioid sarcoma (n=7), extraskeletal myxoid chondrosarcoma (n=5), low-grade fibromyxoid sarcoma (n=4), extraskeletal osteosarcoma (n=3), pleomorphic rhabdomyosarcoma (n=3), spindle-cell/sclerosing rhabdomyosarcoma (n=2), embryonal rhabdomyosarcoma (n=2), angiosarcoma (n=2), clear cell sarcoma (n=1), and malignant solitary fibrous tumor (n=1). The sites of these primary lesions were the extremities (71.8%, n=242) and axial sites (28.2%, n=95). The mean tumor size for all patients was 84.1±55.2 mm (range=2-365 mm), and the FNCLCC classifications were Grade I for 59 patients, Grade II for 138 patients, and Grade III for 140 patients (Table I).
Clinical characteristics of the study participants.
Surgical treatment for the primary tumor was performed in 315 patients (93.5%), and adequate tumor-free margins were achieved in 78.4% (n=247) of the cases. Adjuvant therapy for surgical margin was conducted in 31 patients (9.8%) and included absolute ethanol, hot water, and acridine orange (19, 20). Radiotherapy for the primary tumor was performed in 59 patients (17.5%) and included heavy ion radiation (3.4%, n=2), proton beam radiation (5.1%, n=3), and radiotherapy plus surgery (74.6%, n=44). Chemotherapy was administered to 65 patients (19.3%) and included doxorubicin, ifosfamide, dacarbazine, gemcitabine, docetaxel, methotrexate, cisplatin, vincristine, cyclophosphamide, etoposide, actinomycin D, paclitaxel, eribulin, and trabectedin (Table I).
Distant metastases developed in 108 patients (32.0%), and 91 of these patients developed lung metastases. The sites of extrapulmonary metastases were lymph node (n=21), bones (n=19), soft tissues (n=15), intraperitoneal (n=5), retroperitoneal (n=4), brain (n=4), liver (n=4), thoracic cavity (n=3), mediastinum (n=1), spleen (n=1), and colon (n=1). Sixty-six patients (21.0%) developed local recurrence. The patient outcomes were as follows: no evidence of disease in 215 patients, alive with disease in 42 patients, and 80 patients who died because of their original disease. No patients died due to complications during the perioperative period (Table I).
The multivariate analysis revealed that the size of primary tumor, consultation in a short period after onset, histological high grade, and inadequate surgical margin were significant predictors for poor prognosis for all metastases (p=0.0011, p=0.0325, p=0.0006, and p=0.0151, respectively) (Table II). In addition, the multivariate analysis revealed that the size of primary tumor, axial location, consultation in a short period after onset, histological high grade, and inadequate surgical margin were significant predictors for poor prognosis for lung metastasis (p=0.0167, p=0.0110, p=0.0402, p=0.0002 and p=0.0055, respectively) (Table III). However, in a multivariate analysis of patients with all distant metastases or lung metastasis, the only risk factor for early metastases within 6 months was young age (p=0.0148) (Table IV).
Univariate and multivariate analysis of factors affecting all metastasis-free survival.
Univariate and multivariate analysis of factors affecting lung metastasis-free survival.
Multivariate logistic regression analyses of all and lung early metastasis predictors.
Discussion
This study found that large tumor diameter, histological high grade, short time from onset to consultation, and inadequate surgical margin are risk factors for all distant metastasis and lung metastasis. In addition, the only risk factor for all distant metastasis and lung metastasis early within 6 months after resection of the primary STS was young age.
In STS, some risk factors for distant metastasis or lung metastasis at the time of initial diagnosis or after treatment of the primary tumor have been reported (12-17). Large tumor diameter, histological high grade, and histological type (leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and hemangio-sarcoma) have been reported as risk factors for distant metastasis at the first visit (12, 13). In addition, these factors have also been reported as risk factors for distant metastasis after primary tumor treatment (14, 17). Large tumor diameter and histological high grade were risk factors for distant metastasis in all reports, and our study also included large tumor diameter and histological high grade as risk factors. However, a risk factor that was examined only in our study was the short period from onset to consultation. We think that if the time between noticing a tumor and going to the hospital is short, it is less likely to metastasize because of initiating treatment quickly. However, the results of this study were the opposite. Tumors with a short period from notice to consultation may have been tumors with a high rate of growth and high malignancy.
Insufficient surgical margin was cited as one of the risk factors in our study. There is a report that did not list it as a risk factor even after evaluating it (14). If the tumor is not sufficiently resected during surgery, postoperative radiation or intraoperative adjuvant therapy may be administered, and the presence or absence of such adjuvant therapy may affect the analysis results. This could not be examined because of the number of cases in this study; hence, more detailed examination is necessary in the future.
In our study, the only risk factor for early all distant or lung metastases after treatment of the primary tumor was young age. Large tumor diameter, histological high grade, and inadequate surgical margins, which are risk factors for distant metastasis itself, were predictably listed as risk factors. The reason for higher risk at young age for early lung metastasis is unclear because there are no reports of such studies. This susceptibility could be due to factors involved in hematogenous metastasis being active at younger age and the momentum of tumors being stronger at younger ages. However, further studies are needed to identify the reason.
This is the first study to examine the factors of early distant metastasis after the primary tumor resection in patients with STS. However, there are some limitations as well. In our study, we examined 337 cases, but some reports that examined the risk of distant metastasis in the past included more than 1,000 cases. Because there are various histological types of STS, a larger number of cases is required in order to investigate the effects of histological types as in past reports. Therefore, further detailed studies are needed with a larger number of included patients.
In conclusion, this study evaluated the factors of early all distant and lung metastasis after the primary tumor resection in patients with STS and revealed that the only risk factor was young age, even though large tumor diameter and histological high grade are risk factors for all distant metastasis and lung metastasis. Future studies should focus on the cause of increased risk for early metastasis in young people.
Footnotes
Authors’ Contributions
All Authors were involved in the planning and revising for this research. Tsuchie H, Nagasawa H, Emori M, Murahasi Y, Mizushima E, and Shimizu J collected the clinical data. Tsuchie H analyzed the raw data. Tsuchie H wrote this dissertation. Miyakoshi N and Yamashita T reviewed this manuscript.
Conflicts of Interest
The Authors report no conflicts of interest in relation to this study.
- Received June 3, 2022.
- Revision received July 4, 2022.
- Accepted July 5, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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