eMedicine Specialties > Orthopedic Surgery > Neoplasms

Postradiation Sarcoma

Author: Nagarjun Rao, MD, FRCPath, Assistant Professor, Department of Pathology, Medical College of Wisconsin
Coauthor(s): Donald A Hackbarth Jr, MD, FACS, Professor of Clinical Orthopedic Surgery, Division Chief, Musculoskeletal Oncology, Department of Orthopedic Surgery, Medical College of Wisconsin; Stuart Wong, MD, Assistant Professor, Department of Medicine, Section of Hematology/Oncology, Froedert Memorial Lutheran Hospital; Vivek Panikkar, MBBS, MS, MCh, FRCS, Consulting Surgeon, Departments of Trauma and Orthopedics, Doncaster Royal Infirmary, UK; Vinod B Shidham, MD, FRCPath, FIAC,, Professor, Director of Cytopathology Fellowship Training Program, FNAB Service, and International Cytopathology Fellowship, Department of Pathology, Medical College of Wisconsin; Co-Editor-in-Chief and Executive Editor, CytoJournal
Contributor Information and Disclosures

Updated: Jul 14, 2009

Introduction

Background

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}
 

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

Pathophysiology

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 andinfluence 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).

Clinical

History

Pain is the most common complaint and is abrupt and rapid in onset, relentless and progressive, constant, and worse at night. Pain usually is not relieved with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Mass (soft tissue or bone), bleeding, and pathologic fracture also are reported. Clinical factors that favor a diagnosis of PRS include the following:

• Sarcoma in bone or soft tissue appearing at an unusual age
• Sarcoma in bone or soft tissue at an unusual site
• Addition of intensive chemotherapy to irradiation

Physical

Physical findings are localized to the irradiation area. These usually are a mass (bony or soft tissue), tenderness, and/or a pathologic fracture.

Causes

Causes are discussed in detail in Pathophysiology. While ionizing radiation is the triggering factor (a dose of 40-60 Gy is thought to be the threshold dose), other factors (eg, genetic tendency, concomitant use of chemotherapeutic agents, as yet unknown factors) appear to be responsible for development of PRS.

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