Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA
Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.
Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.
Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.
Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.
Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).
Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.
Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).
The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.
Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.
Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.
Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.
Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.
Disclosures
The authors have no conflicts of interest to disclose.
References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.
2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.
3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.
4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.
5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.
6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.
7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.
8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.
9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.
10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.
11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.
12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.
13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.
14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.
15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.
16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.
17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.