C A S E ST U DY

An unusual cause of knee pain discovered at a nurse practitioner clinic

Janet Kaye Heins, MSN, FNP (Family Nurse Practitioner)1 & Alan Heins, MD, FACEP (Associate Professor)2
1 Gulf Coast Medical Clinic, Robertsdale, Alabama 2 Department of Emergency Medicine, University of South Alabama, Mobile, Alabama

Keywords Non-traumatic knee pain; osteosarcoma; evidence-based guidelines; primary care. Correspondence Alan Heins, MD, FACEP, Department of Emergency Medicine, University of South Alabama, Mobile, AL 36617. Tel: 251-964-7958; Fax: 251-947-9502; E-mail: alan_heins@yahoo.com Received: August 2007; accepted: November 2007 doi:10.1111/j.1745-7599.2008.00355.x

Abstract Purpose: To describe an interesting and instructive case of knee pain from nurse practitioner (NP) practice and discuss the epidemiology, pathophysiology, clinical evaluation, and treatment of osteosarcoma. Data sources: Findings from the history, physical examination, diagnostic testing, and follow-up of the case of an 18-year-old male who rst presented with nontraumatic, diffuse left knee pain of 2.5-month duration. Conclusions: At follow-up, after a trial of conservative treatment, a lesion suspicious for osteosarcoma was seen in the proximal tibia. Osteosarcoma is a rare but dangerous cause of chronic extremity pain, especially in children and adolescents. Implications for practice: NPs must consider malignant bone tumors in the differential diagnosis of traumatic and nontraumatic extremity pain of extended duration, especially in children and adolescents. Thorough, persistent follow-up on recommended tests and referrals is necessary to ensure that important ndings are not missed. The care of uninsured patients requires particular attention to cost concerns and access issues.

Introduction
We report the details of an interesting case from a walk-in/ primary care clinic, operated by two family nurse practitioners in rural Alabama. The University of South Alabama Institutional Review Board reviewed the proposal for this case report and approved it as an exempt protocol, also providing a waiver of subject authorization for use of protected health information. This case report contains several important lessons for nurse practitioners (NPs) in diverse practice settings, especially in primary care and for those working with uninsured and/or socioeconomically disadvantaged patients.

Case report
An 18-year-old male came to the clinic in January 2007 for evaluation of pain in his left knee for the past 2.5 months. He and his family recently moved to Alabama

from another location and did not have health coverage. He complained of pain on ambulation, denied pain at rest, denied any injury, and had no symptoms of paresthesia. He worked as a plumbers assistant, requiring bending and kneeling all day. He did not wear knee pads. He had no allergies to medications. He had no signicant past medical history and took no medicines. He denied alcohol use and smoked tobacco intermittently in social situations. On examination, his gait and station revealed midposition and narrow-base without abnormalities. There was no swelling of the left knee. Range of motion was normal, with no abnormal motion of the joint with anterior and posterior drawer or with varus and valgus stress. He was able to bear weight. He complained of diffuse pain on palpation, but there was no focal tenderness. There was smooth motion of the left patella with exion and extension, but some crepitus was noted. Because of the nonspecic nature of the pain and a plausible diagnosis of prepatellar bursitis, no
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Journal of the American Academy of Nurse Practitioners 20 (2008) 563566 2008 The Author(s) Journal compilation 2008 American Academy of Nurse Practitioners

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fracture or major internal derangement of the knee was suspected and no imaging was recommended at this visit. Patellofemoral syndrome and osteoarthritis were considered but did not seem to t the clinical scenario. He was encouraged to return to the clinic in 1 month. He received a prescription for prednisone 60 mg every morning for 6 days and ibuprofen 600 mg every 8 h as needed for pain and instructed to wear a sports compression bandage for comfort and use knee pads when kneeling at work. The patient did not return to the clinic until 2 months later. He stated that the pain did not ease with the ibuprofen, prednisone, or wearing the knee brace. Because it was not effective, he had not taken ibuprofen for several weeks. The pain had gotten so bad that it was difcult for him to work. He had noted some intermittent swelling of the knee, worse after a long day at work. He had no fever, rash, or other symptoms. On physical exam, gait and station were again without abnormalities. Inspection and palpation of bones, joints, and muscles were unremarkable, except for slight edema to left knee with a small effusion. There was still full range of motion of the left knee. The knee was again stable to anterior and posterior drawer tests and varus and valgus stress. Diagnosis at this visit was left knee pain/bursitis, but we were concerned about the persistence of the pain and poor response to conservative therapy. We began to entertain a differential diagnosis including more serious conditions including occult fracture, osteomyelitis, and cancer. More aggressive care and evaluation were planned. He was encouraged to wear the sports bandage on the left knee, increase the ibuprofen to 800 mg every 8 h, and was prescribed tramadol 50 mg 12 tablets every 6 h for pain. He was told to rest, ice, and elevate the knee. He was instructed to go to a local hospital for a two-view left knee x-ray that we would order for him. He was given a work excuse to return to work 2 days later at full duty. He was instructed to return to the clinic in 1 week if not better. The case was discussed with the collaborating physician, who wrote the prescription for the knee x-ray. We called the patient on the day following his clinic visit and told him that the hospital had his prescription for the x-ray of his left knee and that he should go at his convenience. We tried to follow-up with the patient a week later to see if he had gotten the left knee x-ray but were unable to reach him by home or cell phone. We spoke to the x-ray department at the local hospital and found that the patient had not received the prescribed x-ray. The patient came to the clinic 2 weeks later requesting a rell on his tramadol. He received tramadol 50 mg, #30, 12 tablets every 6 h for pain. He stated that he had been on vacation in another state and had not gotten around to having the knee x-ray. He stated that he would get the x-ray within the next 2 weeks. We again emphasized the
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importance of getting the x-ray to evaluate for serious causes of his knee pain. Approximately 2 weeks later, or 7-weeks following his initial visit, our collaborating physician called the clinic with the radiology report for the x-ray performed that day. The radiologist called our collaborator with the news that the x-ray revealed a large abnormality in the proximal tibia, most likely representing osteosarcoma, but other bone tumors and lymphoma could not be denitively excluded. We immediately tried to call the patient but were unsuccessful at reaching him through all numbers listed on his chart. From discussions with the patient and patients family, we knew that they operated a small business in a nearby town. The authors met at the familys business and notied the patient and his family of the x-ray results. After a lengthy discussion with the patient and his family, the patient decided to go with our physician to an urban, academic, tertiary care hospital with pediatric orthopedic surgery service for admission and further evaluation. That evening, the patient was admitted to the hospital on the service of the pediatric orthopedist. During this initial hospitalization, the patient underwent diagnostic and staging procedures including magnetic resonance imaging (MRI) of the entire leg to determine the extent of soft tissue invasion; computed tomography (CT), with intravenous contrast, of the chest, abdomen, and pelvis to search for distant metastases; technetium bone scan to look for other sites of bone involvement; and open surgical biopsy for tissue diagnosis by a pathologist specializing in bone tumors.

Final diagnosis and case follow-up

Pathologic diagnosis: Osteosarcoma, Grade 4 Clinical diagnosis: Osteosarcoma, locally advanced without distant metastases At the time of writing this article, the patient has undergone two phases of neoadjuvant chemotherapy, initially with high-dose methotrexate and then with cisplatin and doxorubicin. After the chemotherapy, the tumor shrunk some but the extraosseus extension of the tumor continued to impinge on the neurovascular bundle, making limb-sparing surgery less likely to be successful. After prolonged discussions with the patient and his family, he underwent an above-the-knee amputation later that summer. He was treated with Lyrica for phantom limb pain and adjuvant chemotherapy with high-dose methotrexate for an appropriate duration.

Epidemiology
Osteosarcomas are malignant bone tumors characterized by the production of osteoid or immature bone by the tumor cells. In the United States, about 400 cases are

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Unusual cause of knee pain

diagnosed each year, affecting primarily children and adolescents (Gurney, Swensen, & Bulterys, 1999). Osteosarcoma is the fth most common primary malignancy in the age group 1519 and the most common bone cancer in children (Smith, Gurney, & Ries, 1999). Until about 30 years ago, 80%90% of patients died of metastatic disease despite radical surgery for the local tumor. However, effective multimodal adjunctive therapy with surgery, radiation, and chemotherapy can offer longterm survival to about 70% of patients without metastatic disease at diagnosis. Fewer but substantial numbers will be long-term survivors with metastases at the time of diagnosis (Kager et al., 2003).

Pathophysiology
There is no known specic mechanism for the malignant transformation of bone cells into osteosarcoma. Some inherited and acquired defects in the genetic material have been demonstrated to be increased in osteosarcomas. Other bone diseases and environmental factors have been shown to be risk factors for osteosarcoma. The retinoblastoma and p53 tumor suppressor genes are frequently altered in familial and sporadic cases, suggesting a mechanism for the uncontrolled growth of the tumor cells. Patients with other bone diseases such as Pagets disease, benign tumors of bone or cartilage, and chronic osteomyelitis are at increased risk for developing osteosarcoma. Finally, prior cancer treatment with radiation or chemotherapeutic agent is associated with the development of osteosarcomas several years after the treatment of the initial cancer (Malawer, Helman, & OSullivan, 2005).

Clinical presentation
As in the case described above, most patients with osteosarcoma present with several months of localized pain not clearly related to injury in an extremity. Symptoms may uctuate over time but remain localized to one spot. Systemic symptoms of fever, fatigue, or weight loss are rare. Sometimes a tender mass is palpable in the affected area and should be compared to the unaffected limb if possible. Most osteosarcomas are found in the long bones, often the metaphyseal area as in this case. Common sites in order of frequency include the proximal tibia, proximal humerus, distal femur, and other areas of the femur (Wang, Chintagumpala, & Gebhardt, 2007).

Diagnostic evaluation
If suspicious for bone tumor or other destructive bone process, plain x-ray is the best initial test. In the appropri-

ate clinical setting, two thirds of osteosarcomas can be predicted correctly by the nding of a destructive bone lesion with indistinct margins and altered appearance of adjacent bone in a typical location as described above (Malawer et al., 2005). Our patients knee x-ray displayed the typical characteristics, prompting the reading radiologist to call us with his high suspicion for osteosarcoma within minutes of seeing the x-ray. There is good guidance on indications for use of radiographs in acute knee injuries in Stiell et al. (1996). However, few such decision rules or practice guidelines are available for a nonspecic, chronic presentation like our patient. A search of PubMed for practice guidelines on knee pain or bursitis revealed no relevant citation within the past 10 years. A search of the National Guideline Clearinghouse using key words knee pain obtained 68 citations, only one discussing the initial evaluation of knee pain. In the guideline from the American College of Occupational and Environmental Medicine (ACOEM, 2004), the authors recommended plain radiographs for evaluation of suspected red ags, such as constitutional symptoms and signicant mechanism of injury, based on a C level of evidence, dened as limited research-based evidence (at least one adequate scientic study of patients with knee complaints). With the same level of evidence, the authors specically suggested that routine radiographic imaging for most knee complaints or injuries was not recommended. In a resource-constrained environment, especially in screening for an extremely low prevalence disease, liberal use of early radiographs is cost prohibitive and likely harmful. Once a bone tumor is discovered, biopsy of the lesion with pathologist review is the gold standard for distinguishing osteosarcoma from other malignancies and benign conditions. However, before biopsy is performed, a risk stratication and staging evaluation should be conducted. Measurement of serum lactate dehydrogenase should be carried out; high levels are associated with a poor prognosis. Multiple imaging modalities are used to dene the extent of the disease. MRI of the entire involved long bone is used to determine the extent of soft tissue involvement with tumor and is much better than CT scanning for that purpose. CT scanning of the thorax is performed to search for lung metastases; 80% of osteosarcoma metastases are found in the lungs. Finally, technetium-99 bone scans are carried out to detect other bone lesions, another site of second primary or metastatic tumor (Wang et al., 2007). Once staging and pathologic characterization of a biopsy specimen is complete and the diagnosis of osteosarcoma is conrmed, treatment is planned in consultation with medical and radiation oncologists and orthopedic surgeons. In the past, amputation, with wide margins from
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the local tumor, was the treatment of choice. Effective chemotherapy shrinking local tumors and eliminating occult micrometastases has made possible some limb-sparing surgeries with appropriate reconstructive procedures (Carnesale, 1998). Effective chemotherapy in combination with complete surgical resection of local tumor and, if present, isolated pulmonary metastases has increased long-term survival of osteosarcoma patients from 10% to 20% to 50% to 70% compared to surgery alone. The role of adjuvant radiation therapy is not well dened (Kager et al., 2003). The choice of most effective chemotherapeutic agents and timing of chemotherapy remains under investigation. Berend et al. (2001) found no benet from postsurgical chemotherapy compared to no such treatment in a group of patients with locally advanced osteosarcoma who received preoperative chemotherapy and surgical resection. Le Deley et al. (2007) compared a chemotherapeutic regimen with high-dose methotrexate and doxorubicin, similar to that received by our patient, to a regimen with methotrexate, etoposide, and ifosfamide. They found no signicant difference in 5-year survival but suggested that the group receiving etoposide and ifosfamide may benet from avoidance of the toxicity of doxorubicin. Future directions in osteosarcoma research include investigation of proteomic analysis in the diagnosis and staging of these cancers (Bhattacharyya, Byrum, Siegel, & Suva, 2007). In addition, novel treatment strategies with immune-based, target gene, and antiangiogenesis therapies are being investigated (Lamoureux et al., 2007).

needed. The care of uninsured patients requires particular attention to cost concerns and access issues.

Summary and conclusions

Osteosarcoma is a rare but dangerous cause of chronic extremity pain, especially in children and adolescents. The presentation is often nonspecic and diagnosis can be delayed for considerable periods of time. The NP should maintain a high index of suspicion for osteosarcoma and other serious bone and joint diseases in patients with prolonged symptoms, unresponsive to appropriate, conservative therapy. Patient adherence to treatment is a complex process requiring a thorough understanding on the part of the patient of reasons for therapy and exploration of barriers to adherence by the NPs. Systems to ensure followup are critical to achieve highest quality care.

References
American College of Occupational and Environmental Medicine. (2004). Knee complaints. Practice guideline summary. Retrieved October 3, 2007, from http://www.guideline.gov/ Berend, K. R., Pietrobon, R., Moore, J. O., Dibernardo, L., Harrelson, J. M., & Scully, S. P. (2001). Adjuvant chemotherapy for osteosarcoma may not increase survival after neoadjuvant chemotherapy and surgical resection. Journal of Surgical Oncology, 78, 162170. Bhattacharyya, S., Byrum, S., Siegel, E. R., & Suva, L. J. (2007). Proteomic analysis of bone cancer: A review of current and future developments. Expert Reviews in Proteomics, 4, 371378. Carnesale, P. G. (1998). Malignant tumors of bone. In S. T. Canale (Ed.), Campbells operative orthopedics (9th ed., p. 715). Philadelphia: Lippincott. Gurney, J. G., Swensen, A. R., & Bulterys, M. (1999). Malignant bone tumors. In L. A. Ries, M. A. S. Smith, & J. Gurney (Eds.), Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995 (Publication No. 99-464). Bethesda, MD: SEER program, National Cancer Institute. Kager, L., Zoubek, A., Potschger, U., Kastner, U., Flege, S., Kempf-Bielack, B., et al. (2003). Primary metastatic osteosarcoma: Presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. Journal of Clinical Oncology, 21, 20112018. Lamoureux, F., Trichet, V., Chipoy, C., Blanchard, F., Gouin, F., & Redini, F. (2007). Recent advances in the management of osteosarcoma and forthcoming therapeutic strategies. Expert Reviews in Anticancer Therapy, 7, 169181. Le Deley, M. C., Guinebretiere, J. M., Gentet, J. C., Dibernardo, L., Harrelson, J. M., & Scully, S. P.. (2007). SFOP OS94: A randomized trial comparing preoperative highdose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. European Journal of Cancer, 43, 752761. Malawer, M. M., Helman, L. J., & OSullivan, B. (2005). Sarcomas of bone. In V. T. DeVita, S. Hellman, & S. A. Rosenberg (Eds.), Cancer: Principles & practice of oncology (7th ed., pp. 16381671). Philadelphia: Lippincott. Smith, M. A., Gurney, J. G., & Ries, L. A. (1999). Cancer in adolescents 15 to 19 years old. In L. A. Ries, M. A. S. Smith, & J. Gurney (Eds.), Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995 (Publication No. 99-464). Bethesda, MD: SEER program, National Cancer Institute. Stiell, I. G., Greenberg, G. H., Wells, G. A., McDowell, A. A., Cwinn, N. A., and Smith, T. F., . (1996). Prospective validation of a decision rule for the use of radiography in acute knee injuries. Journal of the American Medical Association, 275, 611615. Wang, L. L., Chintagumpala, M., & Gebhardt, M. C. (2007). Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology. UpToDate (www.uptodate.com). Retrieved May 10, 2007, from http://www.utdol.com/utd/ content/topic.do?topickey=Stb_tumor/10616&view=print

Implications for NP practice

NPs must consider malignant bone tumors in the differential diagnosis of traumatic and nontraumatic extremity pain of extended duration, especially in children and adolescents. Evaluation and treatment of nonspecic knee pain should be informed by a thorough history and physical exam and guided by clinical guidelines if available. In this case, the use of prednisone for suspected bursitis was not supported by guidelines investigated in retrospect. However, our pursuit of imaging when red ags arose is supported by evidence-based guidelines (ACOEM, 2004). Thorough, persistent follow-up on recommended tests and referrals is necessary to ensure that important ndings are not missed. NPs should incorporate specic systems to ensure attention to these results is given. Patient adherence to treatment is important if the benets of the NP recommendations are to be achieved. Thorough communication and exploration of barriers to treatment are
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