Postradiation Sarcoma

Postradiation Sarcoma

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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.

Cahan WG. Radiation-induced sarcoma–50 years later. Cancer. 1998 Jan 1. 82(1):6-7. [Medline].

Smith LM, Cox RS, Donaldson SS. Second cancers in long-term survivors of Ewing’s sarcoma. Clin Orthop Relat Res. 1992 Jan. (274):275-81. [Medline].

Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL. Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer. 1998 Jan 1. 82 (1):8-34. [Medline].

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. 2007 Aug. 73(4):521-4. [Medline].

Nicolas MM, Nayar R, Yeldandi A, De Frias DV. Pulmonary metastasis of a postradiation breast epithelioid angiosarcoma mimicking adenocarcinoma. A case report. Acta Cytol. 2006 Nov-Dec. 50(6):672-6. [Medline].

Hanasono MM, Osborne MP, Dielubanza EJ, Peters SB, Gayle LB. Radiation-induced angiosarcoma after mastectomy and TRAM flap breast reconstruction. Ann Plast Surg. 2005 Feb. 54(2):211-4. [Medline].

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].

Fangman WL, Cook JL. Postradiation sarcoma: case report and review of the potential complications of therapeutic ionizing radiation. Dermatol Surg. 2005 Aug. 31(8 Pt 1):966-72. [Medline].

Mullah-Ali A, Ramsay JA, Bourgeois JM, Hodson I, Macdonald P, Midia M, et al. Paraspinal synovial sarcoma as an unusual postradiation complication in pediatric abdominal neuroblastoma. J Pediatr Hematol Oncol. 2008 Jul. 30(7):553-7. [Medline].

Inoue YZ, Frassica FJ, Sim FH, Unni KK, Petersen IA, McLeod RA. Clinicopathologic features and treatment of postirradiation sarcoma of bone and soft tissue. J Surg Oncol. 2000 Sep. 75 (1):42-50. [Medline].

Amendola BE, Amendola MA, McClatchey KD, Miller CH Jr. Radiation-associated sarcoma: a review of 23 patients with postradiation sarcoma over a 50-year period. Am J Clin Oncol. 1989 Oct. 12 (5):411-5. [Medline].

Taghian A, de Vathaire F, Terrier P, Le M, Auquier A, Mouriesse H, et al. Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys. 1991 Jul. 21 (2):361-7. [Medline].

Strauss PG, Schmidt J, Pedersen L, Erfle V. Amplification of endogenous proviral MuLV sequences in radiation-induced osteosarcomas. Int J Cancer. 1988 Apr 15. 41 (4):616-21. [Medline].

Mentzel T, Schildhaus HU, Palmedo G, Büttner R, Kutzner H. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol. 2012 Jan. 25(1):75-85. [Medline].

Laé M, Lebel A, Hamel-Viard F, Asselain B, Trassard M, Sastre X, et al. Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?. Cancer Radiother. 2015 May. 19 (3):168-74. [Medline].

Pitcher ME, Davidson TI, Fisher C, Thomas JM. Post irradiation sarcoma of soft tissue and bone. Eur J Surg Oncol. 1994 Feb. 20 (1):53-6. [Medline].

Smith J. Radiation-induced sarcoma of bone: clinical and radiographic findings in 43 patients irradiated for soft tissue neoplasms. Clin Radiol. 1982 Mar. 33(2):205-21. [Medline].

Neuhaus SJ, Pinnock N, Giblin V, Fisher C, Thway K, Thomas JM, et al. Treatment and outcome of radiation-induced soft-tissue sarcomas at a specialist institution. Eur J Surg Oncol. 2009 Jun. 35 (6):654-9. [Medline].

Bjerkehagen B, Smeland S, Walberg L, Skjeldal S, Hall KS, Nesland JM, et al. Radiation-induced sarcoma: 25-year experience from the Norwegian Radium Hospital. Acta Oncol. 2008. 47(8):1475-82. [Medline].

Kalra S, Grimer RJ, Spooner D, Carter SR, Tillman RM, Abudu A. Radiation-induced sarcomas of bone: factors that affect outcome. J Bone Joint Surg Br. 2007 Jun. 89(6):808-13. [Medline].

Mavrogenis AF, Pala E, Guerra G, Ruggieri P. Post-radiation sarcomas. Clinical outcome of 52 Patients. J Surg Oncol. 2012 May. 105 (6):570-6. [Medline].

Papalas JA, Wylie JD, Vollmer RT. Osteosarcoma after radiotherapy for prostate cancer. Ann Diagn Pathol. 2011 Jun. 15(3):194-7. [Medline].

Weaver J, Billings SD. Postradiation cutaneous vascular tumors of the breast: a review. Semin Diagn Pathol. 2009 Aug. 26(3):141-9. [Medline].

Olson MT, Wakely PE Jr, Weber K, Siddiqui MT, Ali SZ. Postradiation sarcoma: morphological findings on fine-needle aspiration with clinical correlation. Cancer Cytopathol. 2012 Oct 25. 120(5):351-7. [Medline].

General considerations. Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss’ Soft Tissue Tumors. 6th ed. Philadelphia: Elsevier Saunders; 2014. 1-10.

Chan JY, Wong ST, Lau GI, Wei WI. Postradiation sarcoma after radiotherapy for nasopharyngeal carcinoma. Laryngoscope. 2012 Dec. 122(12):2695-9. [Medline].

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Nagarjun Rao, MD, FRCPath Pathologist, Great Lakes Pathologists, Aurora Clinical Laboratories

Nagarjun Rao, MD, FRCPath is a member of the following medical societies: American Society for Clinical Pathology, United States and Canadian Academy of Pathology, College of American Pathologists, Royal College of Pathologists

Disclosure: Nothing to disclose.

Stuart Wong, MD Assistant Professor, Department of Medicine, Section of Hematology/Oncology, Froedert Memorial Lutheran Hospital

Disclosure: Nothing to disclose.

Vivek Panikkar, MBBS, MS, MCh, FRCS Consulting Surgeon, Departments of Trauma and Orthopedics, Doncaster Royal Infirmary, UK

Disclosure: Nothing to disclose.

Vinod B Shidham, MD, FRCPath Professor, Vice-Chair-AP, and Director of Cytopathology, Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Center and Detroit Medical Center; Co-Editor-in-Chief and Executive Editor, CytoJournal

Vinod B Shidham, MD, FRCPath is a member of the following medical societies: American Association for Cancer Research, American Society of Cytopathology, College of American Pathologists, International Academy of Cytology, Royal College of Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Donald A Hackbarth, Jr, MD, FACS Professor of Clinical Orthopedic Surgery, Division Chief, Musculoskeletal Oncology, Department of Orthopedic Surgery, Medical College of Wisconsin

Donald A Hackbarth, Jr, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Association of Tissue Banks, American College of Surgeons, Christian Medical and Dental Associations, Clinical Orthopaedic Society, Children’s Oncology Group, Wisconsin Medical Society

Disclosure: Received honoraria from Musculoskeletal Transplant Foundation for board membership.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Omohodion (Odion) Binitie, MD Medical Director, Assistant Member, Department of Sarcoma, Section Head, Orthopedics, Adolescent/Young Adult and Pediatric Orthopedic Oncology, Medical Director, Physical Therapy, Speech Therapy, and Rehabilitation Services, Assistant Fellowship Program Director, Musculoskeletal Oncology, Moffitt Cancer Center; Assistant Professor, Department of Oncologic Sciences, Department of Ortho and Sports Medicine, University of South Florida Morsani College of Medicine

Omohodion (Odion) Binitie, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, Children’s Oncology Group, Florida Orthopaedic Society, Musculoskeletal Tumor Society

Disclosure: Nothing to disclose.

Postradiation Sarcoma

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