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Nonepithelial Malignancies of the Breast

Nonepithelial Malignancies of the Breast

Drs. Chugh and Baker's concise review highlights disease entities we hear little of, and may never see, but of which we must be cognizant. The article serves as a valuable reminder that not every breast mass that is palpated or detected by radiologic screening represents either a carcinoma or benign entity such as a fibroadenoma. Although rare, the nonepithelial malignancies must be considered in a complete differential diagnosis. Certain "red flags" should raise suspicion. While a new breast mass in a previously irradiated breast most likely represents local recurrence or a new primary, treatment-related sarcoma must be considered. A new breast mass with the mammographic appearance of a fibroadenoma that exhibits particularly rapid growth may be a primary breast sarcoma, phyllodes tumor, or primary breast lymphoma. The treatment and prognosis of these disorders vary dramatically, and therefore, expert pathologic evaluation is essential. Treatment-Related Breast Sarcoma
As the authors point out, very large retrospective series strongly suggest that, in addition to lung cancer and contralateral breast carcinoma, adjuvant radiation for the treatment of breast carcinoma increases the risk of soft-tissue sarcoma, especially angiosarcoma.[ 1,2] Although the relative risk may be high (greater than 15-fold for angiosarcoma), it is essential to appreciate that the absolute risk is very small (perhaps 0.1%).[3,4] When balanced against the proven benefits of adjuvant radiation, the significance is limited. On the other hand, for the unfortunate few who develop a treatmentrelated sarcoma, the outlook is bleak with a median survival of just a few years. When they do occur, treatmentrelated sarcomas develop after a median of 10 years. Clinicians must remain aware of this devastating complication in breast cancer survivors. Early diagnosis with complete resection provides the only hope of longterm survival. Partial Breast Irradiation
If irradiation of healthy breast tissue is a risk factor for breast sarcoma (as well as contralateral breast carcinoma and lung cancer), then it seems desirable to limit the exposure of healthy breast tissue to radiation if this can be achieved without compromising treatment. Traditionally, adjuvant radiation following breastconserving surgery has consisted of irradiation of the whole breast over a 5- to 6-week period. Although outcomes data are still limited, in recent years partial breast irradiation has gained popularity. In partial breast irradiation, a higher dose of irradiation is delivered to a much smaller area (just the immediate region surrounding the lumpectomy cavity) over a much shorter period of time (approximately 5 days), and this can be accomplished by a variety of methods. Interstitial brachytherapy has the longest track record. This technique involves placing catheters into the breast surrounding the lumpectomy cavity and delivering radiation over a few days before removing the catheters. More recently, newer techniques have emerged. The MammoSite was approved by the US Food and Drug Administration in May 2002. MammoSite balloon brachytherapy involves placing a balloon into the tumor bed immediately after resection. The balloon contains a radiation source that irradiates just a 1-cm rim of tissue around the lumpectomy cavity. Three-dimensional conformational external-beam radiation allows partial breast irradiation without catheters or balloons. With intraoperative irradiation, the cavity around a radiation sphere is closed and the entire therapeutic dose is delivered in just 30 minutes. It must be emphasized that partial breast irradiation does not represent standard of care and should only be delivered in the setting of a clinical trial. Most data are confined to phase I and II trials. A major yet unresolved issue involves appropriate patient selection. Most trials to date have included only patients with T1, N0 disease, negative surgical margins, and an absence of multicentric disease or of an extensive intraductal component.[5-8] Breast Sarcoma After Radiation for Nonbreast Malignancies
The references cited above[1-4] and by Drs. Chugh and Baker deal specifically with the risk of developing breast sarcoma following irradiation for breast carcinoma and form the basis for the discussion of the merits of partial breast irradiation. One might logically presume that if radiotherapy for breast carcinoma increases the risk of breast sarcoma, then irradiation of breast tissue for any reason should have a similar effect. However, there is very little evidence to support this theory. The obvious place to look for data would be in a disease treated with chest irradiation that has many longterm survivors, namely, Hodgkin's disease. Although our review of the Hodgkin's data shows evidence for the risk of breast carcinoma, there is a paucity of data suggesting that Hodgkin's irradiation poses a risk of breast sarcoma.[9] The relative risk of breast carcinoma following irradiation for Hodgkin's disease is about 1.5, and this risk is much higher if women are treated at a younger age and with higher doses of radiation. Interestingly, some data suggest that if chemotherapy is added, the radiation risk may be neutralized.[10] We found only one study that mentioned breast sarcoma as a complication after radiation therapy for Hodgkin's disease. In this study, two cases of breast sarcoma were detected among a total of 68 tumors.[11] Moreover, a search of the literature for any data regarding breast sarcoma after radiation given for any reason yielded only one single-patient case report. Drs. Chugh and Baker refer to Lagrange's data[12] when stating that "although therapy-related breast sarcomas are most frequently sequelae of breast carcinoma treatment, they are also associated with the treatment of other malignancies that involve the breast in the radiation field." In Lagrange's paper, 20 years of French data are retrospectively analyzed, focusing on all sarcomas occurring after therapeutic irradiation of a prior malignancy. Of the 80 cases of sarcoma identified, 10 were breast sarcomas, and all 10 developed in patients irradiated for an original diagnosis of breast carcinoma.[12] Therefore, while breast irradiation for any reason may very well be a risk factor for the development of breast sarcoma, the only reasonable volume of objective data we could find was in patients treated for breast carcinoma who have a small but real risk of developing this devastating treatment complication. Primary Non-Hodgkin's Lymphoma of the Breast
Primary non-Hodgkin's lymphoma of the breast is best managed by extrapolating data from non-Hodgkin's lymphoma elsewhere in the body. It is essential to obtain an expert hematopathologic diagnosis so that indolent disease can be correctly distinguished from aggressive disease and managed accordingly. In general, localized indolent disease is managed with local radiation alone, and even though it is accepted that most patients will relapse with distant disease, no proven advantage is associated with systemic therapy until the disease becomes symptomatic. In contrast, aggressive histologies always receive aggressive combination chemotherapy with curative intent, even for apparently localized disease. Most clinicians now routinely add rituximab (Rituxan) to combination cytotoxic therapy. The authors mention ibritumomab tiuxetan (Zevalin). With the recent approval of tositumomab/ iodine-131 tositumomab (Bexxar), there are now two approved radiolabeled antibodies. These agents are currently reserved for use as salvage therapies. In summary, clinicians should remember that nonepithelial breast tumors do occur, albeit rarely. As with other rare entities, there is a paucity of data to guide management decisions and provide prognostic information. When faced with one of these unusual cases, we must make every effort to ensure that what we observe and learn adds to a formalized data pool that will assist our colleagues in the future.

Disclosures

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Huang J, MacKillop WJ: Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 92:172- 180, 2001.
2. Yap J, Chuba PJ, Thomas R, et al: Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 52:1231-1237, 2002.
3. 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 21:361-367, 1991.
4. Karlsson P, Holmberg E, Johansson KA, et al: Soft tissue sarcoma after treatment for breast cancer. Radiother Oncol 38:25-31, 1996.
5. Keisch M, Vicini F, Kuske RR, et al: Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early-stage breast cancer treated with breastconserving therapy. Int J Radiat Oncol Biol Phys 55:289-293, 2003.
6. Polgar C, Fodor J, Major T, et al: Radiotherapy confined to the tumor bed following breast conserving surgery current status, controversies, and future projects. Strahlenther Onkol 178:597-606, 2002.
7. Vicini FA, Kestin L, Chen P, et al: Limited- field radiation therapy in the management of early-stage breast cancer. J Natl Cancer Inst 95:1205-1210, 2003.
8. Polgar C, Sulyok Z, Fodor J, et al: Sole brachytherapy of the tumor bed after conservative surgery for T1 breast cancer: Five-year results of a phase I-II study and initial findings of a randomized phase III trial. J Surg Oncol 80:121-128, 2002.
9. Wolden SL, Hancock SL, Carlson RW, et al: Management of breast cancer after Hodgkin’s disease. J Clin Oncol 18:765-772, 2000.
10. van Leeuwen FE, Klokman WJ, Stovall M, et al: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst 95:971-980, 2003.
11. Cutuli B, Dhermain F, Borel C, et al: Breast cancer in patients treated for Hodgkin’s disease: Clinical and pathological analysis of 76 cases in 63 patients. Eur J Cancer 33:2315- 2320, 1997.
12. Lagrange JL, Ramaioli A, Chateau MC, et al: Sarcoma after radiation therapy: Retrospective multi-institutional study of 80 histologically confirmed cases. Radiology 216:197- 205, 2000.
 
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