Extraskeletal Osteosarcoma of the Breast in an Adolescent Girl Katja Zils,MD,*Florian Ebner, MD,w Michaela Ott, MD,PhD,z Justus Mu ¨ller, MD, PhD,y Daniel Baumhoer, MD, 8 Michael Greulich, MD, PhD, z DetlefRehnitz, MD, PhD,# AndreasRempen, MD, PhD, w Silvia Schaetzle, MD,* Miriam Wilhelm, MD,* and Stefan Bielack, MD, PhD*** Summary: Extraskeletal osteosarcoma (ESOS) is a rare malig- nancy, usually arising in older adults. We were unable to find reports of children or adolescents affected by an ESOS of the breast. Here, we present the case of a high-grade osteosarcoma arising in the breast of a 16-year-old girl. The tumor was treated with breast-conserving resections and adjuvant multiagent che- motherapy, based on a regimen of doxorubicin, high-dose methotrexate, cisplatin, and ifosfamide. At last follow-up, the patient was in first complete remission, 29 months after initial diagnosis. Key Words: extraskeletal osteosarcoma, breast, adolescent and young adulthood oncology (J Pediatr Hematol Oncol 2012;34:e261–e263) E xtraskeletal osteosarcoma (ESOS), first described by Wilson in 1941 1 is a rare disease, comprising much <5% of all osteosarcomas, merely 1% to 2% of all soft tissue sarcomas, and <0.5% to 1% of all breast malignancies. 2,3 The annual incidence of sarcomas of the breast can be estimated at 45 new cases per 10 million women. 4 By definition, ESOS is a malignant mesenchymal soft tissue tumor characterized by the presence of neoplastic osteoid-producing spindle cells without contact to bone or periosteum. 2 The areas most commonly affected by ESOS are the extremities, especially the thighs, but in principle ESOS can arise in any part of the body. ESOS of the breast are rare, but well reported in the literature by multiple case reports and 1 recent larger study by Silver and Tavassoli. 5 Usually patients are older women. Here, we report the case of an adolescent girl. CASE REPORT A 16-year-old girl noticed a painless lump in her left breast. She consulted a gynecologist who considered the mass as harmless and did not initiate further evaluation. Two years later, because of enlargement of the lump, the girl consulted the gynecologist again. There was no significant past medical history such as pregnancies, trauma, or radiation exposure. The patient had no family history of cancer, especially not of breast cancer or other malignancies associated with sarcoma predisposition syndromes. On physical examination, there was a mobile, firm, well- demarcated lump in the inferior-lateral quadrant of the left breast. The overlying skin was normal and axillary lymph nodes were not palpable. The right breast was unremarkable. The patient underwent further evaluation. Breast ultrasound revealed a well-delineated and nonhomogeneous mass measuring 6  5.8  3.7 cm. A punch biopsy was performed. Histologic evaluation revealed a malignant tumor with pleomorphic spindle cells, multiple atypical mitoses, and neoplastic bone and cartilage formation. A sarcomatous carcinoma was excluded due to immunohistochemical negativity against various cytokeratins (AE1/3, KL1, and Cam5.2). The diagnosis of ESOS was made. Additional mammography demonstrated a 9-cm lesion with bizarre calcifications: centrally dense and peripherial fine thread like (Fig. 1A). Computed tomography of the chest including the axilla showed the mass in the left breast but no evidence for metastases (Fig. 1B). Bone metastases were excluded by a bone scan. A breast-conserving tumor resection was performed. Defini- tive histologic examination confirmed the diagnosis of extraskele- tal, high-grade chondroblastic osteosarcoma (Fig. 2). The diagnosis was reconfirmed by 2 independent reference pathologists. Despite of extensive sampling, no areas of sarcomatous carcinoma or phyllodes tumor were detected. All surgical margins were free of tumor, with a minimum distance of 2 mm between tumor and resection margin, corresponding with a marginal resection. Germ- line TP53 was analyzed, but no mutation or deletion was found. After definitive diagnosis, the patient was started on an adjuvant multiagent chemotherapy regimen of doxorubicin, high- dose methotrexate, cisplatin, and ifosfamide. After 10 weeks, reresection was performed to obtain wide margins, as recom- mended for osteosarcoma. The patient underwent subcutaneous mastectomy with breast reconstruction by a transverse-rectus- abdominis-myocutaneous flap. The surgical specimen showed no areas of residual osteosarcoma or other malignancy. Postoperative polychemotherapy was completed over total of 29 protocol weeks. Treatment was complicated by an episode of severe methotrexate toxicity with hypotension, severe abdominal pain, and consecutive compensated renal failure with markedly delayed methotrexate excretion. The patient recovered with appropriate supportive care including glucarpidase and increased and prolonged leucovorin rescue. No further methotrexate was administered; instead, the patient received carboplatin and etoposide. As of April 2011, twenty-nine months after initial diagnosis, the patient remained in first complete remission with no clinically relevant late effects of chemotherapy except for a high-frequency hearing loss. Received for publication May 24, 2011; accepted August 18, 2011. From the *Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart; zBreast Center, Diakonie- Klinikum Stuttgart; wBreast Center Hohenlohe; #Department of Radiology, Diakonie-Klinikum Schwaebisch Hall; zDepartment of Pathology, Caritas-Krankenhaus Bad Mergentheim; yDepartment of Pathology, University Hospital Wuerzburg; **Department of Pediatric Hematology and Oncology, University Children’s Hospi- tal Muenster, Germany; and 8Bone Tumor Reference Center, Institute of Pathology, University Hospital Basel, Switzerland. The authors declare no conflict of interest. Presented in part at the 23th annual meeting of the European Musculo- Skeletal Oncology Society (E.M.S.O.S.), Birmingham, United Kingdom, May 5–7th, 2010. Reprints: Katja Zils, MD, Cooperative Osteosarcoma Study Group COSS, Olgahospital, Pediatrics 5 (Oncology, Hematology, Immu- nology), Klinikum Stuttgart, Bismarckstrasse 8, 70176 Stuttgart, Germany (e-mail: coss@olgahospital-stuttgart.de). Copyright r 2012 by Lippincott Williams & Wilkins CLINICAL AND LABORATORY OBSERVATIONS J Pediatr Hematol Oncol  Volume 34, Number 6, August 2012 www.jpho-online.com | e261