A late effect of ionizing radiation is the development of sarcoma within the field of irradiation, referred to as postradiation sarcoma (PRS). Ionizing radiation has had many varied uses in medicine. In early years, besides being employed in the treatment of a variety of malignancies, radiation was used to treat benign conditions, such as acne, fungal infections, eczema, and various bone diseases.[1, 2, 3, 4, 5, 6, 7, 8, 9]
Advances in cancer treatment in recent years have included intensive multiagent chemotherapy and irradiation.[10] Despite significant medical use of radiation therapy, PRS is an uncommon tumor. The overall incidence of PRS is lower than 1% for patients with cancer who are treated with radiation and survive 5 years.[10] Although the implication for individual patients is significant, little doubt exists that the benefits of ionizing radiation therapy far outweigh the potential risks of developing sarcomas.
The diagnosis of PRS generally is based on the following criteria:
PRS can occur with orthovoltage (low-energy) and megavoltage (high-energy) radiation. With orthovoltage radiation, the dosages are lower and the latent periods longer. The threshold dose for PRS is not known, though in most published series, a dose of 40-60 Gy has been reported.[2, 11, 12] Development of PRS also is influenced by other factors, including genetic tendency and influence of chemotherapeutic agents.
Ionizing radiation is thought to act via genetic alterations, including mutations of p53 and retinoblastoma (Rb) genes. Experimental studies revealed p53 gene alterations or increased p53 messenger ribonucleic acid (mRNA) levels in murine PRS.[13]
A study by Mentzel et al used fluorescence in situ hybridization (FISH) to analyze angiosarcomas and atypical vascular lesions occurring after treatment of breast cancer.[14] In all postradiation cutaneous angiosarcomas, FISH analysis revealed MYC amplification in a variable number of counted nuclei; MYC amplification was not seen in any of the other cases. The authors concluded that MYC amplification may be an important diagnostic tool for distinguishing postradiation cutaneous angiosarcomas from atypical vascular lesions after radiotherapy.
A study by Laé et al found that C-MYC amplification was able to distinguish postradiation breast angiosarcomas from primary breast angiosarcomas, even though the two lesions were morphologically indistinguishable.[15]
Whereas ionizing radiation is the triggering factor (with 40-60 Gy believed to be the threshold dose), other factors (eg, genetic tendency, concomitant use of chemotherapeutic agents, and various factors as yet unknown) appear to be responsible for the development of PRS.
If the criteria listed above (see Background) are followed strictly, the overall US incidence of PRS in patients who survive longer than 5 years following radiation therapy is about 0.1%. In one large series, the incidence was reported to be 0.11% following orthovoltage radiation therapy and 0.09% following megavoltage radiation therapy.[10]
In earlier published studies, many patients had received radiation therapy for benign bone and soft-tissue conditions. In contrast, other reports have shown larger numbers of patients who have received radiation therapy for malignancies such as breast cancer, lymphoma, and Ewing sarcoma.[5, 6, 10, 16]
In a large retrospective study from the Mayo Clinic spread over several decades (1933-1992), benign bone conditions were found to be the single largest group of index lesions in patients with PRS, followed by genitourinary malignancies (especially cervical cancers).[10]
Patients of all ages are affected. In the Mayo study (N = 130), the average age at diagnosis of index lesion was 28.7 years (range, 4 months to 65 years).[10] The mean age at diagnosis of PRS was 47.9 years (range, 10.5-80.9). The latent period ranged from 4 years to 55 years (average, 17). Predilection based on sex has not been reported. In the Mayo study,10 although the male-to-female ratio was 8:5, when sex-specific tumors (eg, breast, cervix, testis, ovary) were excluded, no difference was demonstrated on the basis of sex. A racial predilection has not been reported in the literature.
The overall reported 5-year survival rates for patients with PRS have been poor, ranging from 8.7% to 22% in different studies.[11, 12, 17, 18, 19, 20] However, patients with resectable peripheral lesions at stage IIB or lower have a relatively better prognosis. In the Mayo Clinic series, the 5-year survival rate was 68%.[10] The overall poor prognosis in these patients is thought to be due to a number of interrelated factors, such as the following:
In a retrospective review of histopathologic features, surgery, and outcome in 67 patients with radiation-induced sarcoma followed for a median of 53 months, Neuhaus et al found that median sarcoma-specific survival was 54 months (2-year survival, 75%; 5-year survival, 45%).23 The local relapse rate was 65%, and negative histopathologic margins were a significant predictor of sarcoma-specific survival. Grade and size of tumor approached, but did not attain, significance.
In a study of the prevalence and outcome of radiation-induced sarcomas in 90 sarcoma patients, Bjerkehagen et al reported a sarcoma-related 5-year crude survival rate of 33%.[19] Unfavorable prognostic factors were metastases at presentation, incomplete surgery, and presence of tumor necrosis. According to the authors, complete surgical resection is mandatory for cure.
In a retrospective study of 52 patients with PRS (45 with bone sarcoma and 7 with soft-tissue sarcoma), Mavrogenis et al reported survival figures of 85% at 1 year, 51% at 2 years, 48% at 3 years, and 45% at 5 years.[21] On univariate analysis, sarcoma type was the sole predictor of survival; on multivariate analysis, no variable was a significant predictor of survival.
Clinical Presentation
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