n Case Report

Ewing Superimposed on a Previous in Multiple

Pablo A. Marrero Barrera, MD; Pablo V. Marrero Ortiz, MD

abstract Full article available online at Healio.com/Orthopedics. Search: 20140401-65

It has been reported that patients with hereditary multiple exostoses (called multiple osteochondromatosis by the World Health Organization) are at increased risk for ma- lignant transformation of to secondary . A review of the literature found 14 cases showing transformation of osteochondromas into os- teosarcomas; however, Ewing sarcoma has never been reported superimposed on an osteochondroma. This article presents the case of a boy who underwent biopsy of a previously existent osteochondroma for which the pathology report showed cytologic and immunohistochemical properties consistent with Ewing sarcoma. A 13-year-old boy with hereditary multiple exostoses (multiple osteochondromatosis) presented to an orthopedic clinic because of waxing and waning pain superficial to a previous osteochondroma on the lateral aspect of the right leg, below the knee, of 1 month’s duration. On examination, inflammation was noted over a bony mass associated with tenderness to palpation of the affected area. There was no evidence of penetrating injury or trauma, and the patient reported no constitutional symptoms, including fe- Figure: Radiograph showing multiple osteochon- ver. Radiographs showed marked osteolysis and signs of . Magnetic dromas around the right knee articulation and a resonance imaging showed evidence of cortical erosion and extension of the “moth-eaten” appearance over the fibular head mass into soft tissue. Malignant transformation was suspected, and the patient under- mass. went biopsy. The pathology findings were consistent with Ewing sarcoma. The highly uncommon presentation of this malignancy must serve as a red flag to other physicians who treat patients with hereditary multiple exostoses. Ewing sarcoma tends to be of higher grade and have a worse prognosis than other malignancies that are more com- monly seen in these patients.

The authors are from the Department of Orthopedic , University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico. The authors have no relevant financial relationships to disclose. Correspondence should be addressed to: Pablo A. Marrero Barrera, MD, Department of , University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, Puerto Rico 00936-5067 ([email protected]). Received: August 1, 2013; Accepted: October 9, 2013; Posted: April 15, 2014. doi: 10.3928/01477447-20140401-65

APRIL 2014 | Volume 37 • Number 4 e403 n Case Report

steochondromas are a type of has been shown to increase the risk of ma- benign and are com- lignant transformation, and the fact that an Omonly seen in children and ado- Ewing sarcoma has never been reported lescents. They may be either pedunculated to arise on an osteochondroma make this or sessile, with a cartilaginous cap, and are case particularly interesting. usually located at the most rapidly grow- ing end of the long . Usually these Case Report are isolated lesions, but other patients A 13-year-old boy with a medical his- may have hereditary multiple exostoses tory of multiple osteochondromatosis (HME), also called multiple osteochon- (Figure 1) diagnosed at 1 year presented dromatosis by the World Health Organi- to an orthopedic clinic after being referred zation. This autosomal dominant disorder by his pediatrician for a 1-month history presents with multiple osteochondroma- of recurrent pain and tenderness of the tous lesions. Three related genes have right leg, localized “just below the knee” been implicated in the disorder: EXT1, laterally, just superficial to a previous os- EXT2, and EXT3. EXT1 and EXT2 are teochondroma. The patient stated that the the most common, and EXT1 shows the pain started the morning after he played most severe phenotypes.1 Reported com- a game of basketball with his friends. Figure 1: Radiograph showing multiple osteo- around the right knee articulation and plications associated with osteochondro- He noted that the game was not particu- a “moth-eaten” appearance over the fibular head mas include nerve impingement, limb larly intense, nor did the area receive any mass. length discrepancy, limb deformity, vas- trauma or penetrating injury. He described cular compromise, and decreased range the pain as pulsating, waxing and wan- of motion and pain caused by rubbing of ing, with a pain intensity score of 7 out malaise or weakness, difficulty sleeping, soft tissues over the exostoses. However, of 10 when the pain was the worst. The night sweats, or suppuration over the area the most dreaded complication associ- patient reported no alleviating or exacer- of pain. The patient’s father reported no ated with osteochondromas is malignant bating factors. The pain was associated use of any kind of medication except re- transformation. Fortunately, this seldom with redness, warmth, and swelling over cently. The patient was taking acetamino- occurs. The three most frequent malig- the site. The patient reported no fever, re- phen for the pain and stated that it was not nant bone tumors, in descending order cent weight loss, loss of appetite, general working. of incidence, are parosteal , , and Ewing sarcoma.2,3 Malignant transformation of osteochon- dromatous lesions into chondrosarcomas has been described to have a male-to-fe- male ratio of 2:1, with an average age of onset of 34 years.4-9 For solitary osteochondromas, the risk is less than 1%,10,11 and in patients with HME there is a 2% to 4% chance that chondrosarcoma will develop.1,10,12,13 Only a handful of cases14 have been shown to transform into , and to the authors’ knowledge, Ewing sar- coma has never been reported on a previ- ous bony lesion such as an osteochondro- ma. This report describes the unique case of a 13-year-old boy with HME who was A B found to have Ewing sarcoma on biopsy Figure 2: Anterior (A) and lateral (B) gross preoperative views of the right leg. On physical examination, of a symptomatic osteochondroma. This the patient had erythema, swelling, pain, and warmth to palpation. In addition, a noticeable deformity was patient’s medical history of HME, which present over the fibular head.

e404 ORTHOPEDICS | Healio.com/Orthopedics n Case Report

environmental factors, disease, or trau- ma.15,16 Unlike other cases reported, this report describes Ewing sarcoma superim- posed on a previous osteochondromatous lesion. The location in which the disease manifested itself is also unusual because these malignancies tend to arise from the diaphysis, with only 5.3% occurring in the and 0.5% occurring in the .14 These malignancies are usu- ally high grade,11 requiring more aggres- sive treatment, such as radiation therapy and chemotherapy, as well as early suspi- cion and diagnosis to prevent metastasis to other tissues.15 Unlike Ewing sarcoma, secondary chondrosarcoma, which is composed entirely of cartilaginous tissue, Figure 3: Radiograph showing marked osteoly- Figure 4: Magnetic resonance image showing ex- usually arises from pre-existing benign sis, a sunburst appearance, and Codman triangle tension of the mass to soft tissue and cortical bone chondroid tumors, most typically osteo- sign. erosion. chondromas. It is a low-grade malignan- cy,17 and wide resection alone is usually The patient’s history was negative for normal limits, as were serum lactate de- curative. The prognosis is usually better hospitalizations or surgical procedures. hydrogenase levels. than that for Ewing sarcoma.15,17 In this The family history was positive for mul- After the diagnostic information was re- case, a high level of suspicion and proper tiple osteochondromatosis on the mater- viewed, the patient underwent wide resec- tumor management and protocol led to nal side, with almost all of the patient’s tion of the lesion and bone tissue biopsy. this unlikely diagnosis by biopsy. mother’s family members presenting with The pathology findings showed a light tan Sudden onset of pain associated with multiple osteochondroma lesions. The pa- rubbery mass, which on the cellular level inflammation in a patient with no history tient’s aunt on the father’s side had rheu- showed a small round cell tumor most con- of trauma or obvious cause of pain or ir- matic arthritis since the age of 9 years. sistent with Ewing/primitive neuroectoder- ritation should raise a flag for malignancy, Otherwise, the family history was nega- mal tumor sarcoma. The pathology report especially in the presence of multiple tive for any type of malignancy or disease. also showed adequate resection with clean osteochondromatosis. These symptoms Initial evaluation consisted of physi- margins. Immunohistochemistry findings also suggest , which can re- cal examination, radiographic imaging, further supported the diagnosis, showing semble Ewing sarcoma in presentation, and complete blood count. On physical CD99-positive cells. The patient was given including inflammation, pain, and fever. examination, the patient presented with combined therapy with multidrug chemo- erythema, swelling (Figure 2), pain to therapy and radiation therapy for 1 year. Conclusion light palpation, and marked hardened The patient is currently in remission as It is important to maintain a high level deformity over the right fibular head. Ra- confirmed by computed tomography scans, of suspicion, especially in patients with diographs showed a left proximal fibular whole-body bone scans, and magnetic res- HME, because of the increased risk of mass with marked osteolysis, a sunburst onance imaging since the onset of disease malignancy. The rare presentation of this appearance, and Codman triangle sign 2 years ago. disease raises questions about its etiol- indicative of periosteal reaction (Figure ogy as well as a red flag. Was this case a 3). Magnetic resonance imaging showed Discussion chance phenomenon, or does HME set the clear evidence of cortical bone erosion The principal goal of this case report is environment for gene mutation leading to with extension of the tumor to soft tissue to alert the scientific and medical commu- increased risk of a high-grade malignan- (Figure 4). Technetium bone scan showed nity to a rare presentation of a malignancy cy, such as Ewing sarcoma? Will having avid uptake of radiotracer in the proximal currently believed to arise as a primary le- this malignancy superimposed on an os- 3rd fibular area. Complete blood count sion as a result of spontaneous mutation teochondroma increase the risk of recur- and blood chemistry results were within rather than secondary to a previous lesion, rence in another osteochondroma in this

APRIL 2014 | Volume 37 • Number 4 e405 n Case Report

patient? It is possible that there are other 86:1041-1046. 11. Florez B, Mönckeberg J, Castillo G, Be- guiristain J. Solitary osteochondroma long- 5. Ahmed AR, Tan TS, Unni KK, Collins MS, patients with similar presentation; there- term follow-up. J Pediatr Orthop B. 2008; Wenger DE, Sim FH. Secondary chondrosar- 17(2):91-94. fore, an increased level of suspicion in pa- coma in osteochondroma: report of 107 pa- tients with multiple osteochondromatosis tients. Clin Orthop Relat Res. 2003; 411:193- 12. Schmale GA, Conrad EU III, Raskind WH. is warranted to avoid complications asso- 206. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994; 6. Altay M, Bayrakci K, Yildiz Y, Erekul S, ciated with delayed diagnosis. 76(7):986-992. Saglik Y. Secondary chondrosarcoma in car- tilage bone tumors: report of 32 patients. J 13. Wicklund CL, Pauli RM, Johnston D, Hecht References Orthop Sci. 2007; 12(5):415-423. JT. Natural history study of hereditary mul- tiple exostoses. Am J Med Genet. 1995; 1. Porter DE, Lonie L, Fraser M, et al. Sever- 7. Coley BL, Higinbotham NL. Secondary chon- 55(1):43-46. ity of disease and risk of malignant change drosarcoma. Ann Surg. 1954; 139(5):547-559. 14. Reinus WR, Gilula LA, IESS Committee. in hereditary multiple exostoses: a genotype- 8. Garrison RC, Unni KK, McLeod RA, Radiology of Ewing’s sarcoma: intergroup phenotype study. J Bone Joint Surg Br. 2004; Pritchard DJ, Dahlin DC. Chondrosarcoma Ewing’s sarcoma study. Radiographics. 86(7):1041-1046. arising in osteochondroma. . 1982; 1984; 4:929-944. 2. Unni KK. Chondrosarcoma (primary, sec- 49(9):1890-1897. 15. Ludwig JA. Ewing sarcoma: historical per- ondary, dedifferentiated, and clear cell). In: 9. Hudson TM, Springfield DS, Spanier SS, spectives, current state-of-the-art, and op- Dahlin’s Bone Tumors: General Aspects and Enneking WF, Hamlin DJ. Benign exosto- portunities for targeted therapy in the future. Data on 11,087 Cases. 5th ed. Philadelphia, ses and exostotic chondrosarcomas: evalua- Curr Opin Oncol. 2008; 20:412-418. PA: Lippincott-Raven; 1996:71-108. tion of cartilage thickness by CT. Radiology. 3. Gibbs CP Jr, Weber K, Scarborough MT. Ma- 1984; 152(3):595-599. 16. Grier HE. The Ewing family of tumors. Ew- ing’s sarcoma and primitive neuroectoder- lignant bone tumors. Instr Course Lect. 2002; 10. Bertoni F, Bacchini P, Hogendoorn PC. mal tumors. Pediatr Clin North Am. 1997; 51:413-428. Chondrosarcoma. In: Fletcher CDM, Unni 44:991-1004. 4. Porter DE, Lonie L, Fraser M, et al. Sever- KK, Mertens F, eds. World Health Organiza- ity of disease and risk of malignant change tion Classification of Tumours: Pathology & 17. Lin PP, Moussallem CD, Deavers MT. Sec- in hereditary multiple exostoses: a genotype- Genetics. Tumours of Soft Tissue and Bone. ondary chondrosarcoma. J Am Acad Orthop phenotype study. J Bone Joint Surg. 2004; Lyon, France: IARC Press; 2002:247-251. Surg. 2010; 18:608-615.

e406 ORTHOPEDICS | Healio.com/Orthopedics