Postradiation Sarcoma 

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, in addition to being used 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]} See the image below.

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 less 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 far outweigh the potential risks of developing sarcomas.

The diagnosis of PRS generally is based on the following criteria:

• The histologic features of the original lesion and PRS are completely different.
• PRS is located within the field of irradiation.
• Patients with cancer syndromes such as Li-Fraumeni and Rothmund-Thomson are excluded.
• The latent period (period between initiation of radiotherapy and histologic diagnosis of second neoplasm) is more than 4 years. Although arbitrary given the wide age range reported in the literature (4-55 y), a period of 4 years generally has been accepted as being the lower limit for the latent period.

Recent studies

Neuhaus et al retrospectively reviewed histopathologic features, surgery, and outcome in 67 patients with radiation-induced sarcoma (RIS) treated between 1990 and 2005. Previous breast cancer was the most common indication for radiotherapy. Median time from irradiation to development of RIS was 11 years (3-36 years). Of 67 patients, 34 underwent potentially curative surgery, and microscopically clear margins were achieved in 75% of cases. Pedicled or free tissue transfer was required in 12 patients, and abdominal or chest wall mesh reconstructions were required in 8 patients. Median follow-up was 53 months, and median sarcoma-specific survival was 54 months (2- and 5-year survival: 75% and 45%, respectively). 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.^[11]

Bjerkehagen et al studied the prevalence and outcome of radiation-induced sarcomas (RISs) in 90 sarcoma patients. RIS represented 3% of the sarcomas; median latency time from radiotherapy of the primary tumor to diagnosis of RIS was 13.6 years (range, 2.5-57.8 years). Gynecologic, breast, and testicular cancers were the most common primary diagnoses. For the RISs, 13 histologic types were identified, including 25 malignant fibrous histiocytomas (28% of all cases) and 22 osteosarcomas (24% of all cases). The sarcoma-related 5-year crude survival was 33%, and 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.^[12]

Postradiation sarcoma (PRS) can occur with orthovoltage (low-energy) and megavoltage (high-energy) radiation. With orthovoltage radiation, the dosages are lower and the latent periods are longer. The threshold dose for PRS is not known, although in most published series, a dosage of 40-60 Gy has been reported.^{[2, 13, 14]} 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 evidence shows p53 gene alterations or increased p53 messenger ribonucleic acid (mRNA) levels in murine PRS.^[15]

Frequency

United States

If the criteria listed above are followed strictly, the overall incidence of PRS in patients who survive longer than 5 years following radiation therapy is about 0.1%.^[10] 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 years (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]

Mortality/Morbidity

The reported 5-year survival rate for PRS has been extremely poor, ranging from 8.7-22%.^{[13, 14, 17]} The poor survival rate is thought to be due to a number of interrelated factors, such as the following:

• Significant delay in diagnosis
• Large unresectable lesions
• Older age
• Anaplastic nature of lesions
• Lack of effective adjuvant treatment

Race

A racial predilection has not been reported in the literature.

Sex

Predilection based on sex has not been reported. In the Mayo study, 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.

Age

Patients of all ages are affected. In the Mayo study, which involved 130 patients, the average age at diagnosis of index lesion was 28.7 years (range 4 mo to 65 y).^[10] The mean age at diagnosis of PRS was 47.9 years (range 10.5-80.9 y). The latent period ranged from 4 years to 55 years (average 17 y).