JOURNAL OF CLINICAL ONCOLOGY DIAGNOSIS IN ONCOLOGY

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1 VOLUME 30 NUMBER 33 NOVEMBER JOURNAL OF CLINICAL ONCOLOGY DIAGNOSIS IN ONCOLOGY Lymph Node Metastasis of Osteosarcoma Case Report A 19-year-old man presented with a 12-month history of a swollen left thigh. There was no history of trauma, fever, or other joint abnormalities. On referral to his orthopedic surgeon, the patient underwent several imaging studies. A presumptive diagnosis of a primary malignant bone tumor of the left femur with inguinal lymph node metastases was made, and the patient was referred to our hospital for additional evaluation and treatment. Physical examination showed that the left thigh was swollen and warm, with an extensive hard mass in the medial midthigh. No lymph nodes were palpated throughout the lower extremities. The initial radiograph of the left femur showed a bone formation associated with a periosteal reaction that extended from the midpoint to distal end of the femoral shaft (Fig 1). Axial, gadolinium-enhanced, fat-suppressed, T1-weigheted magnetic resonance imaging (MRI) showed marrow involvement and a large circumferential soft tissue mass encasing the femoral neurovascular bundle (Fig 2A, arrowhead). Coronal MRI showed intramedullary involvement encompassing almost the entire left femur (Fig 2B). Thallium-201 scintigraphy demonstrated increased uptake in the left thigh during both early and late phases. Whole-body bone scintigraphy showed a high uptake of technetium-99m methylene diphosphonate throughout most of the left femur as well as in the left inguinal region (Fig 3). Computed tomography (CT) of the pelvis confirmed the presence of a small, calcified mass at the external iliac lymph node (Fig 4). CT of the chest and abdomen was normal. Histologic examination of a core-needle biopsy from the femoral lesion confirmed the diagnosis of conventional osteosarcoma of the osteoblastic type. On the basis of these findings, a femoral osteosarcoma with an isolated external iliac lymph node metastasis was diagnosed. The patient was treated with neoadjuvant chemotherapy that consisted of six courses of high-dose methotrexate (12 g/m 2 ) and two courses of cisplatin (120 g/m 2 ) and adriamycin (ADR; 30 g/m 2 per day for 2 days). After preoperative chemotherapy, slightly decreased bulk and increased ossification of the left femoral mass with formation of a peripheral bony shell was observed on radiography. MRI also showed a decrease in the diameter of the soft tissue mass. Thallium-201 scintigraphy revealed markedly decreased uptake in the lesion. In addition, the accumulation on the bone scintigraphy was localized primarily at the midpoint of femoral shaft, and disappeared at the inguinal region. CT of the pelvis revealed increased ossification of the external iliac lymph node. No metastases were found in the lungs or abdomen of the patient. Preoperative chemotherapy was judged to have achieved a partial response. Sixteen weeks after the diagnosis was made, the patient underwent a curative procedure that consisted of simultaneous resection of the left femoral lesion and lymph node metastasis. The patient was placed in a lateral position on the operating room table to allow anterior and posterior rolling. A long postero- Fig 1. Journal of Clinical Oncology, Vol 30, No 33 (November 20), 2012: pp e345-e349 e345

2 Hattori and Yamamoto A B Fig 2. lateral incision was curved to the medial aspect of the distal femur and knee joint. The sciatic nerve was identified and preserved. The greater trochanter, along with both abductors and the vastus lateralis, was osteotomized to be fixed to the prosthesis, exposing the hip joint and acetabulum. The external rotators were dissected, and the capsule was opened circumferentially. The femur was dislocated anterolaterally, and the psoas and adductor muscles were serially dissected. The distal femur was approached between the rectus femoris and vastus medialis. The knee joint capsule was opened, and the cruciate ligaments, collateral ligaments, and capsular and muscular attachments to the distal femur were resected. The femoral nerve was ligated at the level of hip joint. The femoral vessels were also ligated at the levels of both the hip joint and popliteal space. The entire femur was resected en block along with the vastus medialis and intermedius muscles (Fig 5A). The tibial osteotomy was performed in the same manner as a standard knee joint arthroplasty. The vastus lateralis, rectus femoris, patella, and patellar tendon were preserved. After resection, the defect was reconstructed with a total femoral prosthesis, and both arterial and e346 venous reconstructions were performed with synthetic grafts (Fig 5B; postoperative radiograph of the femur). To reconstruct the hip capsule, the remaining capsule was covered with an artificial ligament, and the external rotators and psoas muscles were sutured tightly around the prosthesis neck to provide stability. The left external iliac lymph node was resected by using a second incision. Histologic examination confirmed that the surgical margins of both the femoral lesion and the lymph node metastasis were negative. Tumor necrosis rates were reported as 70% to 80% for the primary lesion and greater than 90% for the metastatic lesion (Fig 6; photomicrograph of the external iliac lymph node metastasis of osteosarcoma shows the deposition of osteoid with a few viable tumor cells [white arrowhead] and lymphoid tissue [black arrowhead], high power). After the surgery, infection with methicillin-resistant Staphylococcus aureus developed around the incision, along with a subcutaneous hematoma in the left thigh. After a 14-day course of both intravenous vancomycin and gentamycin administration, the left thigh, which had become more swollen as a result of the associated JOURNAL OF CLINICAL ONCOLOGY

3 Diagnosis in Oncology Fig 4. per day and 2 g/m2 per day for 6 days; total, 16 g/m2 per week) combined with mesna at the same dose as ifosfamide, two courses of high-dose methotrexate, and a course of cisplatin and ADR. However after one cycle of postoperative chemotherapy, multiple pulmonary metastases were detected by using a chest CT scan. The patient refused additional treatment, such as new chemotherapy regimens and a metasectomy. The patient died 14 months postoperatively as a result of pulmonary complications. According to the original schedule for neoadjuvant chemotherapy, we were to start postoperative chemotherapy 2 weeks after the surgery. This delay in postoperative chemotherapy may have lead to the development of lung metastases. Fig 3. infection, decreased in size. Moreover, levels of inflammatory markers returned to normal ranges. Six weeks after the surgery, the patient received postoperative chemotherapy, including two courses of high-dose ifosfamide (4 g/m2 Discussion Clinically detectable metastatic disease at initial diagnosis occurs in less than 20% of patients with conventional osteosarcoma.1-3 Osteosarcoma generally spreads hematogenously, and the most common site of metastases is the lungs, followed by the bones.1-6 Meanwhile, an autopsy study conducted by Hatori et al7 demonstrated the possibility of lung metastases via the lymphatic route in multifocal osteosarcoma (MOS). The authors suggested that the route of metastasis (hematogenous or lymphogenous) in MOS needed to be clarified. In two large series of patients with conventional metastatic osteosarcoma at initial presentation, the occurrence of clinically detectable lymph node metastases was found to be rare, with a prevalence of less than 4.0%.1,4 Few authors have reported histologic subtypes in their descriptions of lymph node metastases of conventional osteosarcoma; however, nine of 10 cases reported in several studies were of the osteoblastic type.8-12 Lymph node metastases seem to be more common in conventional osteoblastic osteosarcoma than in other histologic subtypes. The minimum work-up for primary metastases generally includes CT of the chest and whole-body bone scintigraphy. CT is the best modality for early detection of lung metastases. Whole-body bone scintigraphy is most useful for evaluating distant osseous metastases. Bone scintigraphy has also been widely used for the detection of e347

4 Hattori and Yamamoto A B Fig 5. extrapulmonary metastases from osteosarcoma, often detecting disease before other imaging modalities. In previously reported cases of osteosarcoma with metastatic calcified lymph nodes, the lesions were detected with bone scintigraphy.8-13 However, Kim et al14 reported that lymph node metastases could not be detected with bone scintigraphy as a result of noncalcified metastatic lymph nodes. In addition, e348 Vo lker et al15 reported that whole-body imaging with positron emission tomography by using fluorine-18-fluorodeoxyglucose (FDG) as a tracer (FDG-PET) was an excellent method for accurately detecting lymph node metastases in patients with pediatric sarcoma. Regarding the detection of bone metastases, FDG-PET and bone scintigraphy were equally effective in patients with osteosarcoma because of JOURNAL OF CLINICAL ONCOLOGY

5 Diagnosis in Oncology AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. Fig 6. osteoblastic activity and the production of osteoids, whereas FDG- PET was superior to bone scintigraphy in patients with Ewing sarcoma family tumors. FDG-PET may be capable of detecting noncalcified metastatic lymph nodes in osteosarcoma. The development of effective neoadjuvant chemotherapies has dramatically improved the prognosis of patients with localized disease at presentation, leading to a cure rate of 50% to 70% Moreover, although surgery formerly involved amputation in most cases, local treatment now consists of limb salvage in more than 80% of patients. 19,20 However, the prognosis of patients with metastatic osteosarcoma at initial presentation remains poor, with 5-year survival rates of approximately 20%, despite the use of aggressive surgery combined with multiagent chemotherapy. 1-6 Prognosis correlates significantly with the site of metastases. The number and distribution of nodules within the lung have been reported to predict prognosis, with better outcomes for patients with unilateral deposits and a low number of metastases. However, the prognosis for extrapulmonary metastatic osteosarcoma, in which the primary metastatic site is bone, remains poor. 1-6 The prognosis of patients with lymph node metastases of osteosarcoma is not well established because this type of metastasis is rare. With the combination of the minimal data available in the literature, only two of 21 patients with osteosarcoma with lymph node metastases remained alive after initial diagnosis. 1,3,4,6 In these studies, lymph node involvement in patients with osteosarcoma at initial presentation seemed to confer extremely poor prognosis. With our patient, we deferred the initial postoperative chemotherapy because of a surgical site infection. This delay may have resulted in a poor outcome. Hiroyuki Hattori and Kengo Yamamoto Tokyo Medical University, Tokyo, Japan REFERENCES 1. Kager L, Zoubek A, Pötschger U, et al: Primary metastatic osteosarcoma: Presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21: , Kaste SC, Pratt CB, Cain AM, et al: Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: Imaging features. Cancer 86: , Meyers PA, Heller G, Healey JH, et al: Osteogenic sarcoma with clinically detectable metastasis at initial presentation. J Clin Oncol 11: , Bacci G, Briccoli A, Rocca M, et al: Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: Recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 14: , Daw NC, Billups CA, Rodriguez-Galindo C, et al: Metastatic osteosarcoma. Cancer 106: , Harris MB, Gieser P, Goorin AM, et al: Treatment of metastatic osteosarcoma at diagnosis: A Pediatric Oncology Group Study. J Clin Oncol 16: , Hatori M, Ohtani H, Yamada N, et al: Synchronous multifocal osteosarcoma with lymphatic spread in the lung: An autopsy case report. Jpn J Clin Oncol 31: , English R, Dicks-Mireaux C, Malone M, et al: Osteosarcoma Presumed lymph node metastases in two cases. Skeletal Radiol 18: , Madsen EH: Lymph node metastases from osteoblastic osteogenic sarcoma visible on plain films. Skeletal Radiol 4: , Nouyrigat P, Berdah JF, Roullet B, et al: Osteosarcoma with calcified regional lymph nodes. Pediatr Radiol 23:74-75, Tobias JD, Pratt CB, Parham DM, et al: The significance of calcified regional lymph nodes at the time of diagnosis of osteosarcoma. Orthopedics 8:49-52, Zwaga T, Bovée JV, Kroon HM: Osteosarcoma of the femur with skip, lymph node, and lung metastases. Radiographics 28: , Arkader A, Morris CD: Lymphatic spread of pagetic osteogenic sarcoma detected by bone scan. Cancer Imaging 8: , Kim SJ, Choi JA, Lee SH, et al: Imaging findings of extrapulmonary metastases of osteosarcoma. Clin Imaging 28: , Völker T, Denecke T, Steffen I, et al: Positron emission tomography for staging of pediatric sarcoma patients: Results of a prospective multicenter trial. J Clin Oncol 25: , Bacci G, Briccoli A, Ferrari S, et al: Neoadjuvant chemotherapy for osteosarcoma of the extremity: Long-term results of the Rizzoli s 4th protocol. Eur J Cancer 37: , Bielack SS, Kempf-Bielack B, Delling G, et al: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20: , Saeter G, Wiebe T, Wiklund T, et al: Chemotherapy in osteosarcoma. The Scandinavian Sarcoma Group experience. Acta Orthop Scand Suppl 285:74-82, Lindner NJ, Ramm O, Hillmann A, et al: Limb salvage and outcome of osteosarcoma. The University of Muenster experience. Clin Orthop Relat Res 358:83-89, Bacci G, Ferrari S, Lari S, et al: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84:88-92, 2002 DOI: /JCO ; published online ahead of print at on October 1, e349

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