AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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}

Advances in cancer treatment in recent years have included intensive multiagent chemotherapy and irradiation.⁹ 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.⁹ 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.

Pathophysiology

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 is reported.^{2, 10, 11} Development of PRS also is influenced by other factors, including genetic tendency, influence of chemotherapeutic agents, and as yet unknown factors.

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.¹²

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%.⁹ In one large series, the incidence was reported to be 0.11% following orthovoltage radiation therapy and 0.09% following megavoltage radiation therapy.⁹ 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, 9, 13} 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).⁹

Mortality/Morbidity

The reported 5-year survival rate for PRS has been extremely poor, ranging from 8.7-22%.^{10, 11, 14} The poor survival rate is thought to be due to a number of interrelated factors, as follows:

• Significant delay in diagnosis
• Large unresectable lesions
• Elderly
• 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 based on sex was demonstrated.

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).⁹ The mean age at diagnosis of PRS was 47.9 years (range 10.5-80.9 y). The latent period ranged from 4-55 years (average 17 y).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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.

DIFFERENTIALS

Section 4 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to Be Considered

Differential diagnoses for bone pain in a patient with a history of irradiation include the following:

• Metastatic bone disease
• Radiation osteopathy
• Nonneoplastic causes of bone pain, such as rotator cuff impingement syndrome, osteoarthritis, bursitis/tendonitis, gout, and pseudogout

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• No specific laboratory blood tests are used to diagnose PRS. Routine laboratory investigations may be ordered.
• Cytogenetic studies on PRS tumor cells do not have much value because the tumor cells can have numerous quantitative (numerical) and qualitative abnormalities that lack specificity. However, the value of cytogenetic analysis lies in excluding other conditions that may have specific anomalies and that may present a challenge in light microscopic examination.

Imaging Studies

• Plain radiographs
• • Obtain plain radiographs in 2 planes.
  • Cortical bone destruction is the most common finding.
  • A mineralized soft tissue mass is seen in most patients.
  • Changes such as osteopenia and sclerosis are seen in a minority of patients.
• CT scan and MRI
• • If plain radiograph findings are normal and the patient has significant pain, these scans are useful for identifying abnormal areas in the medullary cavity, cortical bone destruction, and the presence of an extramedullary soft tissue mass.
  • MRI is the best modality to detect soft-tissue involvement in PRS.
  • CT scan of the chest is performed to detect pulmonary metastases.
• Technetium bone scan is performed to detect bone metastases.

Procedures

• Biopsy
• • Fine-needle aspiration biopsies or Tru-Cut core biopsies can be obtained from the lesion for histopathologic/cytopathologic confirmation of diagnosis and to type and grade the lesion.
  • In the case of a deep-seated lesion, CT-guided biopsies can be obtained.
  • The biopsy should be the final diagnostic procedure because it can distort imaging studies, especially MRI.
  • Careful preoperative planning is required before biopsy is attempted. Imaging studies aid the surgeon in selecting the best site for tissue diagnosis. Usually, the best diagnostic site is at the interface between the tumor and adjacent normal tissue; this also prevents the occurrence of fracture at the biopsy site, as biopsy in this location usually does not violate cortical bone.
  • A frozen section can be obtained to determine if adequate representative tissue has been obtained. A definitive diagnosis usually is delayed until permanent sections are analyzed.

Histologic Findings

Postradiation sarcoma (PRS) in bone and soft tissue usually is a high-grade lesion, which partly accounts for the almost uniformly grim prognosis.^{4, 7} In a study of 130 patients with PRS of bone and soft tissue from the Mayo Clinic, osteosarcoma was the most common type, constituting 61.5% of all cases.⁹ This was followed by fibrosarcoma (23.7%), malignant fibrous histiocytoma (MFH, 9.6%), chondrosarcoma (3.7%), and rare cases of angiosarcoma and Ewing sarcoma. No difference in histologic type of PRS was demonstrated between the orthovoltage and megavoltage groups.

Among soft-tissue PRS lesions, the most common histologic type is MFH (70%), followed by osteosarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, and angiosarcoma.¹⁵

Grossly, these tumors are soft and fleshy, with extension into adjacent soft tissue and formation of a soft-tissue mass. Hemorrhagic/necrotic foci and matrix production (osteoid/chondroid) may be seen. Degenerative calcific changes also may be noted.

Microscopically, while specific characteristics such as osteoid production (in osteosarcomas) may be seen, in general, these tumors show pleomorphic high-grade spindle cell features with marked nuclear pleomorphism, mitotic activity, and variable necrosis (see Image 1).

Staging

Careful staging is a prerequisite for appropriate management of PRS.

The marrow extent and soft-tissue involvement of PRS should be gauged using radiologic modalities, of which MRI is the best choice. Biopsies may be obtained to confirm the diagnosis and to type and grade the lesion.

A CT scan of the chest is obtained to detect pulmonary metastases. A technetium bone scan is performed to detect bone metastases.

Based on the results of imaging and histopathologic/cytopathologic studies, the lesion may be staged. The American Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS) staging systems generally are used.

• The AJCC staging system is based on the TNM staging system and uses the following categories:
• • Size and extension of primary tumor (T)
  • Involvement of lymph nodes (N)
  • Presence of metastases (M)
  • Type and grade of sarcoma (G)
• Definitions of the TNMG staging system are as follows:
• • T - Primary tumor
    • T1 - Tumor smaller than 5 cm
    • T2 - Tumor 5 cm or larger
  • N - Regional lymph nodes
    • N0 - No histologically verified regional node metastasis
    • N1 - Histologically verified regional node metastasis
  • M - Distant metastasis
    • M0 - No distant metastasis
    • M1 - Distant metastasis
  • G - Histologic grade of malignancy
    • G1 - Well differentiated
    • G2 - Moderately well differentiated
    • G3 - Poorly differentiated
    • G4 – Undifferentiated
• The MSTS staging system classifies tumors as follows:
• • Stage IA - Low grade, intracompartmental
  • Stage IB - Low grade, extracompartmental
  • Stage IIA - High grade, intracompartmental
  • Stage IIB - High grade, extracompartmental
  • Stage III - Systemic or regional metastases
• In the MSTS staging system, the margins are classified as follows:
• • Intralesional - Margin through tumor tissue
  • Marginal - Margin through reactive zone around tumor consisting of edema, inflammatory cells, fibrous tissue, and tumor cell satellites
  • Wide - Margin through normal tissue outside reactive zone
  • Radical – Removal of entire compartment containing tumor

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

PRS ideally is managed with a multidisciplinary approach with input from the radiation oncologist, medical oncologist, and surgeon. Because PRS is high grade and advanced stage or metastatic at the time of diagnosis, patients commonly are not eligible for curative surgery, and the prognosis for these patients generally is poor. Chemotherapy is the most common treatment modality and typically is associated with poor response rates.

Surgical Care

Surgical options for PRS include wide or radical resection (limb salvage) or amputation and depend upon the stage and location of the tumor and the age and performance status of the patient. In patients with peripherally located tumors at stage IIB and below (MSTS system), it is feasible to expect resection to provide a reasonable 5-year survival rate. (In one study, the 5-year survival rate for this group approached 68%.) Brachytherapy or postoperative external beam radiation can be added if the margins are close to the tumor.

Consultations

A multidisciplinary approach is ideal for PRS. The surgical oncologist, who preferably has experience in treating sarcomas, should be involved at the outset for the diagnostic evaluation. In addition, input from the radiation oncologist and medical oncologist is necessary to achieve a coordinated treatment plan, particularly for patients in whom combined modality treatment is being contemplated.

Diet

Nutrition is an important aspect in the care of patients receiving active cancer treatment.¹⁶ Surgery, radiation therapy, and chemotherapy may adversely affect the patient's nutritional status and hence may alter quality of life. Cancer treatment can alter the patient's ability to eat, digest, and absorb food. Anticipation of these potential adverse effects, therefore, is necessary. Intervention, such as with commercially available liquid nutritional supplements, may be required to maintain adequate caloric intake. Consultation with a health care provider qualified in nutrition also may be considered.

Activity

The impact of physical activity upon treatment outcome in patients with cancer is not well defined in the literature. However, modest levels of physical activity during cancer treatment may provide benefits with respect to increasing appetite, maintaining mobility and muscle tone, and enhancing a sense of emotional well being.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

The selection of chemotherapy agents used to treat patients with PRS largely is based upon data from clinical trials of soft tissue and bone sarcomas. The 2 most active single chemotherapy agents are Adriamycin (doxorubicin) and ifosfamide. These agents have roughly equivalent activity. Dacarbazine (DTIC) has modest single-agent activity. MAID (combination of mesna, Adriamycin, ifosfamide, and DTIC) has been a commonly used combination chemotherapy regimen for the treatment of soft tissue sarcoma over the past decade.

Three randomized trials have been performed in which regimens containing Adriamycin and ifosfamide were compared with Adriamycin alone. Two of these trials showed higher response rates in the treatment arms containing Adriamycin and ifosfamide than in those containing Adriamycin alone. However, the Adriamycin and ifosfamide combinations also were associated with significantly higher myelosuppression (including fatal neutropenic sepsis) but no survival advantage. No standard of care has been established for the choice of chemotherapy agents. Therefore, treatment typically is individualized.

Preoperative chemotherapy can be administered with or without radiation therapy and is administered either intravenously (as a bolus or as a continuous infusion) or regionally via an intraarterial infusion to an isolated limb. Preoperative chemotherapy generally is considered in order to facilitate a limb-sparing procedure. This approach is considered for patients who otherwise would require amputation for cure or palliation. In some instances, this approach may be considered to convert a marginally resectable lesion into one that is operable. Consideration of preoperative chemotherapy for PRS must take into account that response rates to chemotherapy are low and that most long-term survivors with PRS are patients who have undergone successful surgical resection.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Further Inpatient Care

• Inpatient care frequently is required for patients with PRS at different stages of treatment. Inpatient care may be required for diagnostic evaluation to allow surgery with general anesthesia. Most preoperative chemotherapy regimens and palliative chemotherapy regimens for advanced disease require inpatient hospitalization.

Further Outpatient Care

• Radiotherapy is delivered in the ambulatory setting. Follow-up of patients who have received definitive treatment for PRS is individualized based upon the site of disease. Generally, follow-up should include a posttreatment imaging study to provide a baseline against which subsequent studies may be compared. Subsequent follow-up should include a thorough history and physical examination, with laboratory tests and chest radiographs and other imaging performed regularly for the first 2 years. Assessments may be spaced further apart after the second year to the fifth year following definitive treatment. Annual assessments may be performed thereafter.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• Lowering the dosage of radiation and/or adjuvant chemotherapy is the only preventive measure for PRS; however, this may not be practicable. The discontinuation of radiation for benign bone and soft-tissue diseases has limited PRS to patients receiving radiation treatment for malignancies.

Complications

• PRS is a complication of radiation treatment for various bone and soft-tissue malignancies.
• Complications that arise from PRS are those seen with other soft-tissue and bone tumors, such as pathologic fractures, hemorrhage, metastases, and local complications due to direct invasion.

Prognosis

• The overall reported 5-year survival rates for patients with PRS have been poor, ranging from 8.7-22% in different studies.^{10, 11, 14} 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%.
• The overall poor prognosis in these patients is related to delayed diagnosis, large unresectable lesions, poor response to chemotherapy, and high-grade histology.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Light microscopic appearance of postradiation osteosarcoma; tumor is composed of pleomorphic plump spindle cells with focal presence of neoplastic osteoid (pink areas) in between tumor cells. This meningeal tumor occurred 10 years postradiation in a patient who had received radiation for a recurrent pituitary neoplasm.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

1. Cahan WG. Radiation-induced sarcoma--50 years later. Cancer. Jan 1 1998;82(1):6-7. [Medline].
2. Smith LM, Cox RS, Donaldson SS. Second cancers in long-term survivors of Ewing''s sarcoma. Clin Orthop. Jan 1992;(274):275-81. [Medline].
3. Cahan WG, Woodard HQ, Higinbotham NL, et al. Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer. Jan 1 1998;82(1):8-34. [Medline].
4. Debeer P, Van de Meulebroucke B, Stuyck J, Sciot R, Samson I. Postradiation soft tissue sarcoma of the shoulder: a case report. Acta Orthop Belg. Aug 2007;73(4):521-4. [Medline].
5. Nicolas MM, Nayar R, Yeldandi A, De Frias DV. Pulmonary metastasis of a postradiation breast epithelioid angiosarcoma mimicking adenocarcinoma. A case report. Acta Cytol. Nov-Dec 2006;50(6):672-6. [Medline].
6. Hanasono MM, Osborne MP, Dielubanza EJ, Peters SB, Gayle LB. Radiation-induced angiosarcoma after mastectomy and TRAM flap breast reconstruction. Ann Plast Surg. Feb 2005;54(2):211-4. [Medline].
7. Fang Z, Matsumoto S, Ae K, Kawaguchi N, Yoshikawa H, Ueda T. Postradiation soft tissue sarcoma: a multiinstitutional analysis of 14 cases in Japan. J Orthop Sci. 2004;9(3):242-6. [Medline].
8. Fangman WL, Cook JL. Postradiation sarcoma: case report and review of the potential complications of therapeutic ionizing radiation. Dermatol Surg. Aug 2005;31(8 Pt 1):966-72. [Medline].
9. Inoue YZ, Frassica FJ, Sim FH, et al. Clinicopathologic features and treatment of postirradiation sarcoma of bone and soft tissue. J Surg Oncol. Sep 2000;75(1):42-50. [Medline].
10. Amendola BE, Amendola MA, McClatchey KD, et al. Radiation-associated sarcoma: a review of 23 patients with postradiation sarcoma over a 50-year period. Am J Clin Oncol. Oct 1989;12(5):411-5. [Medline].
11. Taghian A, de Vathaire F, Terrier P, et al. Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys. Jul 1991;21(2):361-7. [Medline].
12. Strauss PG, Schmidt J, Pedersen L, et al. Amplification of endogenous proviral MuLV sequences in radiation- induced osteosarcomas. Int J Cancer. Apr 15 1988;41(4):616-21. [Medline].
13. Pitcher ME, Davidson TI, Fisher C, et al. Post irradiation sarcoma of soft tissue and bone. Eur J Surg Oncol. Feb 1994;20(1):53-6. [Medline].
14. Smith J. Radiation-induced sarcoma of bone: clinical and radiographic findings in 43 patients irradiated for soft tissue neoplasms. Clin Radiol. Mar 1982;33(2):205-21. [Medline].
15. Enzinger FM, Weiss SW. General considerations. In: Soft Tissue Tumors. 3rd ed. St. Louis:. Mosby;1995.
16. Brown J, Byers T, Thompson K, et al. A cancer journal for clinicians: nutrition during and after cancer treatment. In: A Guide for Informed Choices by Cancer Survivors. Vol 51. 2001.

Article Last Updated: Feb 22, 2008