A previously healthy 17-year-old girl presents to the emergency department (ED) with left-knee pain and leg swelling. Pain and swelling started in the left knee approximately 3 months prior, after competing in a road race. Two weeks before her arrival in the ED, she visited an urgent care center and was diagnosed with patellar tendinitis. Radiograph and magnetic resonance imaging (MRI) of the knee at that time yielded negative findings for fracture, malignancy, or thrombus.There is no history of trauma, surgery, recent travel, estrogen-containing medications, or immobility before her presentation to the urgent care center and the ED. The patient denies any history of sexual activity. Family history is significant for a factor V Leiden mutation in the maternal aunt.The patient’s heart rate is 87 beats per minute; respiratory rate, 16 breaths per minute; blood pressure, 107/56; and temperature, 97.5 °F; and she is 100% on room air. Physical examination reveals a well-appearing girl in no respiratory distress, and lungs are clear to auscultation bilaterally. Abdominal examination is positive for active bowel sounds and negative for tenderness to palpation, hepatosplenomegaly, and masses. She has clear asymmetry of the lower extremities, with her left leg demonstrating swelling and warmth. Her left calf circumference is 3 cm larger than her right calf circumference. There is tenderness with compression of the left gastrocnemius. Pedal pulses are appreciated bilaterally.Due to worsening knee pain and swelling, she presents to the ED for evaluation. Given concerns for deep venous thrombosis (DVT), Doppler ultrasonography is performed, with significant results for DVT extending from the posterior tibial veins to the common femoral vein. She begins low-molecular-weight heparin and is admitted to the hospital. The pediatric hematology service is consulted for further management.Laboratory evaluation with complete blood count, comprehensive metabolic panel, γ-glutamyl transpeptidase (GGT), parathyroid hormone, and vitamin D yields negative findings except for an elevated alkaline phosphatase level of 1847 units/L (reference range, 0–187 units/L). D-dimer value was not obtained.A vascular surgery specialist is consulted for evaluation for possible thrombectomy given the extent of the thrombus. A CT of the abdomen, pelvis, and chest performed to define the vasculature and clot burden reveals the inciting etiology.Unilateral leg pain with swelling has an expansive differential (Table 1). An extensive venous thromboembolism (VTE) without a clear inciting etiology raises concern for an inherited prothrombotic state such as protein C and S deficiency, antithrombin deficiency, factor V Leiden mutation, and prothrombin gene mutation. Inherited thrombophilias could cause an extensive thrombus even without an inciting trigger such as trauma, estrogen-containing contraceptives, or recent surgery. While the patient has no first-degree relatives with known inherited thrombophilias, her mother could be heterozygous for factor V Leiden mutation and asymptomatic. Factor V Leiden is inherited in an autosomal dominant manner, raising the possibly of the patient also being heterozygous for the mutation. Given the extent and location of her VTE, an anatomical variant of iliac vein obstruction syndrome (May-Thurner syndrome) was considered. Iliac vein obstruction syndrome involves the narrowing or occlusion of the iliac vein, producing venous symptoms, such as pain or edema, and can result in DVT.1 This narrowing could be from forces external to the vein such as malignant germ cell tumors or sarcomas, benign mature teratomas, pregnancy, or cysts. A specific subset, May-Thurner syndrome, is an anatomical condition in which the external compression of the left common iliac vein by the right common iliac artery produces similar symptoms and extensive left-sided DVTs. However, venous thromboembolic events are acute in their presentation, which is not consistent with the patient’s timeline of symptoms. Elevated alkaline phosphate levels are not associated with DVT but can be seen in liver-related (eg, cirrhosis, hepatitis) or bone-related diseases (eg, fracture, malignancy).The patient underwent abdominal and pelvic CT and was found to have a large mass (12 × 8 × 9.5 cm) arising from the left ilium, causing displacement of the abdominal contents and compression of the iliac vessels (Figure 1). Chest CT demonstrated widespread metastatic disease to the lungs. CT imaging results were discussed with family and patient, and a second abdominal examination was performed with patient guidance revealing a barely palpable mass in the left lower quadrant. She subsequently underwent a biopsy of the pelvic lesion, which revealed a high-grade osteosarcoma. Skeletal scintigraphy did not demonstrate evidence of osteoblastic metastatic disease.Osteosarcoma occurs most frequently in teenagers and often presents with pain and swelling at the site developing over weeks to months. It has only rarely been associated with DVT at the time of diagnosis. Although osteosarcoma can be associated with certain cancer predisposition syndromes (eg, Li-Fraumeni, Bloom, retinoblastoma gene 1 mutation), it occurs spontaneously in most cases.2 Approximately two-thirds of presentations occur in the appendicular skeleton, and only 8% occur in the pelvis.2 Initial evaluation of the primary site with radiograph and MRI along with metastatic evaluation of the lungs with CT imaging is necessary to measure the extent of disease. Definite diagnosis is made through lesional biopsy. Bone marrow biopsies are not routinely performed, given a very low likelihood of bone marrow involvement.Neoadjuvant chemotherapy with high-dose methotrexate, doxorubicin, and cisplatin (MAP) is delivered before limb-sparing surgery, after which adjuvant MAP is continued.3 Osteosarcoma is generally not sensitive to radiation therapy. Despite aggressive therapy, overall survival is approximately 70% but will decrease to 25% with metastatic or unresectable disease at diagnosis.4Staging revealed multiple bilateral pulmonary nodules. She completed neoadjuvant and adjuvant MAP chemotherapy per the Children’s Oncology Group AOST0331 protocol. She underwent limb-sparing complete resection of the primary tumor as well as resection of all detectable pulmonary nodules. She received therapeutic anticoagulation with rivaroxaban throughout her treatment.DVT is an unusual but described presentation of solid tumors.Pain, typically dull, and swelling of an extremity persisting for weeks to months should raise concern for malignancy. Masses can cause DVTs by compressing the vein and/or triggering a hypercoagulable state from the malignant tumor.Acute pain and swelling in an extremity should raise concern for DVT. Extensive left-sided lower extremity clot raises concerns for iliac vein obstruction syndrome, specifically May-Thurner syndrome.Osteosarcoma primarily arises in the appendicular skeleton and is treated with neoadjuvant limb-sparing surgery and adjuvant surgery.Osteosarcoma overall survival is approximately 70% but decreases to approximately 25% with metastatic or unresectable disease at presentation.Delineation between hepatic and nonhepatic etiologies of alkaline phosphatase elevations can be assessed by obtaining GGT values, which are elevated in hepatic causes.
Bujold et al. (Mon,) studied this question.