Japanese Journal of Clinical Oncology Advance Access originally published online on July 15, 2005
Japanese Journal of Clinical Oncology 2005 35(8):444-452; doi:10.1093/jjco/hyi128
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© 2005 Foundation for Promotion of Cancer Research
Incidence of Multiple Primary Malignancies in a Cohort of Adult Patients with Soft Tissue Sarcoma
1 Diagnostic Radiology Division, 2 Pathology Division and 4 Orthopedic Surgery Division, National Cancer Center Hospital and Institute, 3 Statistics and Cancer Control Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo and 5 Department of Orthopedic Surgery, Kyushu Cancer Center, Fukuoka, Japan
For reprints and all correspondence: Ukihide Tateishi, Division of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan. E-mail: utateish{at}ncc.go.jp
Received March 6, 2005; accepted June 1, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: Some studies to date have suggested the development of multiple primary malignancies in patients with soft tissue sarcoma. The current study was performed to quantify the risk of development of multiple primary malignancies in adult patients with soft tissue sarcoma.
Methods: A total of 406 consecutive patients who were diagnosed with soft tissue sarcoma were identified in the study analysis. The cumulative incidence of multiple malignancies was calculated by comparing Kaplan–Meier curves and log-rank tests from each histological type. A Cox proportional hazards model was used to estimate the influence on the hazard ratio (HR) of each variable.
Results: A total of 35 patients with soft tissue sarcoma (9%), having preceding (n = 15) and subsequent (n = 20) malignancies other than soft tissue sarcoma were documented. The 5- and 10-year estimated cumulative incidence of multiple primary malignancies were 7.6 and 12.3%, respectively. The hazard risk of multiple primary malignancies adjusted for potential confounding variables was significantly associated with age at diagnosis (HR = 1.51, P = 0.0019). The risk of multiple primary malignancies was also increased in patients with myxofibrosarcoma adjusted by the potential confounding variables (HR = 2.34, P = 0.048). The 5- and 10-year estimated cumulative incidence of multiple primary malignancies in patients with myxofibrosarcoma were both 16.9%.
Conclusion: The results of our study confirm that the risk of multiple malignancies appears to be impacted by age at the time of diagnosis of the first tumor and by the histological type of myxofibrosarcoma.
Key Words: soft tissue sarcoma • myxofibrosarcoma • multiple malignancies • second primary tumor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The development of multiple malignancies in a single individual has been reported after successful treatment of primary tumors (1,2). The greatest attention has been focused on second primary tumors (SPTs) after treatment of malignant lymphoma (3), retinoblastoma (4) and malignant germ cell tumor (5,6) because good cure rates have been achieved for many years, resulting in many long-term survivors.
The occurrence of multiple malignancies in patients with soft tissue sarcoma (STS) has also been reported (7,8). Studies focused on patients with osteosarcoma have revealed an overall 10-year cumulative incidence of SPT of 2.0–3.1% (9,10). Adult patients with STS have been found to develop other malignant neoplasms either before or after the diagnosis of STS, and this phenomenon occurred at a significantly higher rate than reported for the occurrence of STS in the general cancer population (11).
However, the risk of SPT after treatment of the first tumor has been mainly described in children with STS. Although we have observed the occurrence of multiple primary malignancies that occurred in adult patients with various histological types of STS, especially pleomorphic malignant fibrous histiocytoma (MFH) and myxofibrosarcoma, in daily clinical practice there has been little information on the management of these patients. The current study was therefore undertaken to assess the risk of development of another primary malignant tumor in adult patients with STS.
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MATERIALS AND METHODS |
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PATIENTS
The records of 500 consecutive adult STS patients diagnosed and treated between February 1962 and August 2003 were retrieved from the pathology files of our institution. This study was approved by the local Ethics Committees after confirmation of informed consent by the patients to a review of their records and images. The enrollment criteria consisted of (i) adult STS patients whose pathological specimens and medical charts were available for review; and (ii) patients who were not lost to follow-up. The exclusion criteria consisted of (i) subjects whose pathological specimens and medical charts were insufficient for review; and (ii) subjects whose pathological subtypes were considered to be rare in the clinical setting. Thus, 94 patients (19%) whose tumors comprised epithelioid sarcoma (n = 25), alveolar soft part sarcoma (n = 20), clear cell sarcoma (n = 16), extraskeletal myxoid chondrosarcoma (n = 20) or extraskeletal osteosarcoma (n = 13) were excluded from the analysis, and the 406 patients with common STSs were included in the analysis. The patients consisted of 223 men and 183 women, and they ranged in age from 16 to 87 years (median age: 53 years). During the period 1962–2003, the concept of MFH or myxofibrosarcoma changed. Twenty-three myxofibrosarcomas (34%) which were previously diagnosed as myxoid variant of MFH or solely fibrosarcoma were reclassified by the review of pathological examinations. Autopsy was performed in 16 cases (4%) and their pathological specimens were also available for review.
In the patients who developed multiple primary malignancies, we investigated: age at diagnosis, gender, family history, anatomic site, tumor size, depth, surgical margin, histological type, MIB-1 score, grade, whether chemotherapy has been performed, whether radiation therapy has been performed and the outcome. If the patient had died, the date and the cause of death were also noted.
Patients were followed-up with regard to survival until August 31, 2004, at which time 250 patients were alive with no evidence of disease, 26 patients were alive with disease and 130 patients had died of their disease. The malignancy-free survival period (MFSP) was measured from the date of diagnosis of STS to the date of the first observations of multiple malignancies. If the detection of malignancy other than STS preceded the date of diagnosis of the STS, the MFSP was recorded as 0. If a patient was alive without developing any multiple malignancies at the last visit, the data on MFSP were censored as of the date when the survival was confirmed. If a patient died without detection of other primary malignancies, the MFSP was censored at the date of death. If other primary malignancy was found at autopsy, the date of death was treated as an event.
Histological slides of the primary tumors of all patients were reviewed for diagnosis by two experts. Whenever necessary, immunohistochemistry was used to confirm the diagnosis or tumor type according to the WHO classification (12). MIB-1 immunostaining was performed to grade all tumors. An MIB-1 score of 1 was assigned to lesions with an MIB-1 labeling index (LI) of 0–9%, an MIB-1 score of 2 was given to lesions with an MIB-1 LI of 10–29%, and an MIB-1 score of 3 was given to lesions with an MIB-1 LI 
30%. There were tumors with an MIB-1 score of 1 (n = 140; 35%), 2 (n = 62; 15%) and 3 (n = 204; 50%). The histological grade is a three-grade system obtained by adding the scores for tumor differentiation, tumor necrosis and MIB-1 score, each of which was given a score of 0–3 (13). By using the grading system, tumors corresponded to grade 1 (n = 128; 32%), grade 2 (n = 107; 26%) and grade 3 (n = 171; 42%), respectively. Tumor depth was measured relative to muscular fascia that had been invaded and was characterized as superficial or deep. The vast majority of lesions (n = 322; 79%) were deep seated, and 94 tumors were superficial.
STATISTICAL ANALYSIS
Univariate analysis of the cumulative incidence of multiple malignancies was performed by comparing Kaplan–Meier curves and log-rank tests from each histological type. The hazard ratio (HR) of each variable was estimated by using a Cox proportional hazards model in the univariate and multivariate analyses. The following factors are considered as potential confounding factors for the incidence of multiple malignancies: age at presentation, gender, family history of malignant neoplasm, anatomic site, tumor size, depth, surgical margin, histological type, MIB-1 score (1, 2 or 3) and grade (1, 2 or 3). Variable selection by the backward elimination (
= 0.2) procedure was performed in the multivariate analyses. All analyses were performed with SAS Software (version 6.12; SAS Institute, Cary, NC).
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RESULTS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Tumors had a diameter >5 cm in 302 patients (74%). Most tumors were located in the extremities (n = 244; 60%) compared with the trunk (n = 96; 24%) and other sites (n = 66; 16%). The histological types consisted of liposarcoma (n = 159; 39%), myxofibrosarcoma (n = 67; 17%), pleomorphic MFH (n = 53; 13%), synovial sarcoma (n = 50; 12%), leiomyosarcoma (n = 32; 8%), malignant peripheral nerve sheath tumor (MPNST; n = 25; 6%) and fibrosarcoma (n = 20; 4%). Of these 406 tumors, 371 tumors (91%) did not develop multiple malignancies (Table 1).
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A total of 35 patients (9%) with STS were documented in the study population, among whom the STS was preceded by (n = 15) and followed by (n = 20) malignancies other than STS. The median age at the time of diagnosis of the first tumors was 63 years (range 39–79 years). The SPTs were diagnosed a median of 64 months after the diagnosis of the first tumor. A third primary tumor (TPT) was found in eight patients, a median of 127 months after the first tumor. One patient was found to have a fourth primary tumor 331 months after the first tumor. The overall 5- and 10-year estimated cumulative incidence of multiple primary malignancy was 7.6% [95% confidence interval (CI) 4.7–10.4] and 12.3% (95% CI 7.4–18.0), respectively.
Information related to the patients is listed in Table 2. The most frequent histological types of STS were myxofibrosarcoma (n = 13; 19.4%) and pleomorphic MFH (n = 6; 11.3%). Less common histological types consisted of fibrosarcoma (n = 2; 10%), liposarcoma (n = 11; 6.9%), leiomyosarcoma (n = 2; 6.3%) and MPNST (n = 1; 4%).
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The risk of multiple malignancies differed significantly according to the histological type of the STS (log rank test: P = 0.0055). None of the patients with synovial sarcoma had multiple malignancies. The multivariate analysis adjusted for potential confounding variables showed a higher risk of multiple malignancy in patients with myxofibrosarcoma (Table 3). When patients with pleomorphic MFH and myxofibrosarcoma were combined into the same histological category, the risk of multiple malignancies was 2.13 (95% CI 1.00–4.55, P = 0.0496). However, no significant association was found between risk of multiple malignancies and survival rate, or familiar history of malignant neoplasm in pleomorphic MFH and myxofibrosarcoma.
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Twelve patients (37.1%) had a family history of cancer. One patient had familial adenomatous polyposis (FAP) with a germline mutation in the APC gene. Two patients with a second or third primary STS had previously received systemic chemotherapy and radiation therapy. Patients with a second or third primary cancer whose STS preceded it had previously received chemotherapy (n = 3) and radiation therapy (n = 4). Only one patient had a third primary cancer within the radiation field.
Age at the time of diagnosis was associated with increased risk of multiple malignancies in the unadjusted analysis (HR = 1.52, 95% CI 1.17–1.97, P = 0.0016), but no significant association was found with gender, family history of cancer, MIB-1 score, grade, tumor size, depth or margin. Furthermore, no interaction was evidenced between the risk of multiple malignancies and having received chemotherapy or radiation therapy.
Myxofibrosarcoma developed as the first tumor in three patients, the second tumor in seven, the third tumor in two, and the fourth tumor in one (Table 4). The MFSP between the diagnosis of the first and second malignancies ranged from 4 to 275 months (median: 69.0 months). The TPTs were detected within 142 months after the diagnosis of the first tumor. One myxofibrosarcoma of the thigh developed after radiation therapy for a second primary esophageal carcinoma. The fourth primary tumor developed in a patient who had undergone surgical resection three times for carcinomas of the colon and cecum. The patient developed a myxofibrosarcoma of the thigh that was treated by surgery and chemotherapy 120 months after the diagnosis of the SPT. The 5- and 10-year estimated cumulative incidence of multiple malignancies in patients with myxofibrosarcoma were both 16.9% (95% CI 7.8–26.1; Fig. 1). The overall survival time of the 13 patients in the group after the diagnosis of the first tumor ranged from 10 to 408 months (median: 148.0 months). The 5-year survival rate of the group was similar to that of the patients without multiple malignancies (84.6 versus 89.3%, P = 0.81).
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Pleomorphic MFH occurred as the first tumor in five patients (Table 5), and in one patient it was followed by esophageal carcinoma. The MFSP between the diagnosis of the first and second malignancies varied from 17 to 94 months (median: 74.0 months). The 5-year estimated cumulative incidence of multiple malignancies in patients with pleomorphic MFH was 10.2% (95% CI 0.0–20.6; Fig. 1). The overall survival time of the six patients in this group ranged from 48 to 155 months (median: 113.0 months), and the 5-year survival rate was not significantly different from that of pleomorphic MFH patients without multiple malignancies (50.0 versus 51.6%, P = 0.32). One patient died of the first tumor after developing a metastasis, and the other five patients died of the SPT.
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Nineteen multiple malignancies were associated with four types of adult STSs: liposarcomas in 11 patients, fibrosarcomas in two, leiomyosarcomas in two and MPNST in one (Table 6). The MFSP between the diagnosis of the primary malignancy and the second malignancy ranged from 1 to 141 months (median: 60.0 months). The 5- and 10-year estimated cumulative incidence of multiple malignancies in this group was 5.1% (95% CI 2.2–8.0) and 9.7% (95% CI 3.8–15.7%; Fig. 1), respectively. The overall survival time of the 16 patients from the time of diagnosis of the first tumor ranged from 6 to 223 months (median: 96.5 months). No significant difference in 5-year survival rate was found between the patients with and without multiple malignancies (66.1 versus 71.6%, P = 0.80).
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The objective of this study was to review the incidence of multiple malignancy in adult STS patients. The results of the analysis showed that 9% of the patients had multiple malignancies. The 5- and 10-year estimated cumulative incidence of multiple malignancy was 7.6% (95% CI 4.7–10.4) and 12.3% (95% CI 7.4–18.0), respectively. In addition, the risk of multiple malignancy appeared to be impacted by age at the time of diagnosis of the first tumor and by the histological type of myxofibrosarcoma.
The results of this analysis add to the evidence of an association between STS and the risk of multiple malignancy. The results are consistent with the findings in the cohort study Merimsky et al. that assessed the risk of multiple malignancies associated with STS (11). In their study, 28 of 375 adult patients (7.5%) with STS were found to have developed another primary malignant neoplasm either before or after the diagnosis of STS, a significantly higher rate than reported for the occurrence of STS in the general cancer patient population (1.0%). In addition, they also observed an association between primary MFH and the occurrence of renal cell carcinoma. However, Merimsky et al. did not evaluate risk according to histological types of STS, and they included several patients with bone sarcoma in their analysis. Thus, our study expanded on the findings of Merimsky et al. by assessing the impact of histological type.
Previous studies in patients with STS have found frequencies of an SPT ranging from 1.2 to 6.0% (14,15). In contrast, one study that investigated the risk of developing SPT in patients with non-Hodgkin lymphoma yielded a frequency of 15.4% (16). However, the populations in these studies were mainly children or adolescents. In our study, the rate of association of an SPT or TPT with STS was 9.0%, suggesting that the frequency of multiple malignancies is similar in the different age populations. Age at the time of diagnosis was strongly associated with increased risk of multiple malignancies in adult patients with STS.
The results of our study showed that the risk of multiple malignancies was similar when the analysis was conducted separately for patients with pleomorphic MFH and myxofibrosarcoma, the most common types of STS. Multiple malignancies were detected in six patients with pleomorphic MFH, and in five patients where the pleomorphic MFH was preceded by another malignant tumor. Similarly, the other malignancy was detected first in three of the 13 patients (23%) with myxofibrosarcoma and subsequently in the other 10 patients (77%). Some investigators consider a pleomorphic MFH to be a high grade tumor that has a substantially high metastatic rate and poor prognosis (17,18). Myxofibrosarcoma is a distinct fibroblastic neoplasm that may recur and has a relatively poor prognosis (19–21). In our study, univariate analysis revealed that no significant association was found between risk of multiple malignancy and survival rate, or familiar history in pleomorphic MFH and myxofibrosarcoma.
A family history of cancer and genetic predisposition to cancer may be associated with a risk of multiple malignancies. A correlation between the incidence of multiple malignancy and familial aggregation has been demonstrated in Li–Fraumeni syndrome (22). Similarly, genetic factors have an impact on the risk of various histological types of SPT (23,24). It was not likely that these factors would profoundly influence the risk related to development of multiple malignancies since there was no significant association between familial history of cancer and the risk of multiple malignancies in our study. Some rare familial syndromes are associated with an excess risk of multiple malignancies. There was a patient with FAP with a germline mutation of the APC gene. This patient developed myxofibrosarcoma of the thigh as a fourth primary tumor after surgical treatment of colon cancers three times.
Despite the fact that the known carcinogenic effects of chemotherapy and radiation therapy are associated with an increased risk of developing SPT (25,26), no interaction was found with having received chemotherapy and radiation therapy according to the results of the multivariate analysis. The lack of agreement between our findings and those of other investigators may be attributable to the small number of patients treated by chemotherapy and radiation therapy: only two patients with second or third primary STS were previously treated by chemotherapy and radiation therapy.
Our results showed that multiple malignancies occurred in 9% of patients with STS, and that the rate of occurrence depended on the histological type. The 5-year survival rate of patients with multiple malignancies according to the histological type of STS was not statistically different from that of the patients without multiple malignancies. Many histological types of multiple malignancies occurred in various organs, suggesting that the whole-body screening to detect other primary malignant neoplasms in addition to local recurrence or distant metastasis should be considered in the management of patients with multiple primary malignancies. Recent prospective studies have highlighted the potential diagnostic role of whole-body [18F]fluorodeoxyglucose positron emission tomography (FDG PET) for evaluation of malignant tumors. FDG PET is an accurate non-invasive test for diagnosis of adult STS and has high sensitivity and intermediate specificity for malignancy. We recommend a whole-body FDG PET scan in the search for a second malignancy in patients with multiple primary malignancies.
In summary, the results of our study confirm the incidence of multiple primary malignancies in adult patients with STS, and the histological type of myxofibrosarcoma was found to be associated with an increased risk of multiple primary malignancy. Physicians should be aware of the increased risk of multiple primary malignancies in patients with myxofibrosarcoma, and whole-body screening to detect other malignant neoplasms is desirable.
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References |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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