case studies

case studies case study [cytology | hematology | immunology]

A Swollen Painful Knee In An Elderly Man With Recently Diagnosed Acute Myelogenous Leukemia Satish K. Solanki, MD, Shahnila Latif, MD, Diana M. Veillon, MD, Mary L. Nordberg, PhD, Steven J. Saccaro, MD, James D. Cotelingam, MD, Seth M. Berney, MD Louisiana State University Health Sciences Center, Shreveport, LA DOI: 10.1309/YRU7L787AVRKTCVL

Patient 60-year-old Caucasian male.

[I1] Medial aspect of our patient’s left knee (note degree of swelling in comparison to his right knee).

Chief Complaint Sudden onset of severe pain and swelling in the left knee, right ankle, and right great toe, 1 day after initiation of chemotherapy for recently diagnosed acute myelomonocytic leukemia (AML-M4). Medical History This patient had no past history of arthritis. Prophylactic treatment with allopurinol was started prior to initiation of chemotherapy with daunorubicin and cytarabine. Physical Examination On examination, the patient was afebrile, normotensive (blood pressure, 120/70 mmHg); and the left knee, right ankle, and right great toe were warm to the touch, tender to palpation, and had effusions. In addition, the left knee was swollen [I1]. Gross and Microscopic Histologic Finding Under aseptic conditions, 18.0 mL of turbid fluid was aspirated from the left knee. Microscopically, no crystals were detected under polarized light. Gram stain and microbial cultures were negative. The WBC and RBC counts were 3,285/mm3 and 360/mm3, respectively. However, atypical mononuclear cells were identified on light microscopy [I2]. Flow cytometric immunophenotyping of synovial fluid cells from our patient was performed with the results shown in I3.

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Questions: 1. What is the interpretation of this patient’s flow cytometric immunophenotyping results? 2. Based on the constellation of this patient’s clinical and laboratory findings, what is the most likely diagnosis? 3. Which age group is most commonly affected by this patient’s condition or disorder? 4. What is the usual clinical presentation of this patient’s condition? 5. What is the pathogenesis of this patient’s condition? 6. What is the preferred diagnostic test for establishing the diagnosis of this patient’s condition? 7. What is the best therapy for this patient’s disorder? Answers: 1. A predominance of myelomonocytic cells which expressed CD10, CD11b, CD13, CD14, CD15, CD33, CD38, myeloperoxidase, and HLA-DR [I3]. These results were similar to those obtained during a prior bone marrow evaluation. The presence of CD13+/CD14- and CD13+/CD14+ cells is a characteristic finding in acute myelomonocytic leukemia. 2. Most likely diagnosis: leukemic arthritis. Any form of arthritis may occur in patients with leukemia. Therefore, the diagnosis of this condition may be difficult,

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published. Arthritis is rarely an initial manifestation of acute leukemia in adults. However, in children with arthritis, leukemia is an important consideration and should be excluded since failure to diagnose leukemic arthritis may be associated with a significant delay in treatment.5,8 The prevalence of leukemic arthritis in relation to specific types of leukemia is unknown. However, arthritis is more frequently a complication of childhood than adult leukemia, where the incidence varies between 12% to 65% in children versus 4% to 13% in adults.9,10

[I2] Nucleolated leukemic cells with delicate chromatin and cytologic atypia (Wright-Giemsa stain; 1,000x magnification) observed on microscopic examination of our patient’s synovial fluid.

and prior to considering leukemic arthritis as the cause of joint swelling in a patient with leukemia, infectious and crystalline forms of arthritis must be excluded. Moreover, the type and severity of the leukemia, the therapy, and its effect on the immune system significantly influence the differential diagnosis. In clinical practice, joint infections and crystalinduced arthritis are observed more frequently than leukemic arthritis.1-4 3. Arthritis is a well-known complication of leukemia in both children and adults.5,6 Seward reported the first case in 1930.7 Since then, many case reports and series have been

5. Synovial infiltration by leukemic cells is considered the predominant pathogenic mechanism for the occurrence of leukemic arthritis. This mechanism is supported by the observation that leukemic arthritis subsides as the disease remits and reappears as the disease relapses.10 Other possible mechanisms include a synovial reaction to periosteal or capsular infiltration, hemarthrosis, and immune complexinduced synovitis. Recently, an increased amount of interleukin-1 beta (IL-1β) secreted by an overexpanded B

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4. One or more painful and swollen joints. Moreover, the signs and symptoms of leukemic arthritis may appear before, after, or concurrent with the diagnosis of leukemia.5,11,12 Arthritis is commonly asymmetric, pauciarticular, and may be either insidious or of sudden onset. Its manifestations may be additive or migratory and most frequently large joints are involved; however, other joints may also be involved.9,13 In addition, joint pain may be intermittent or persistent and the severity of the pain is frequently out of proportion to the observed inflammation.5 Bone pain in leukemia is caused by expansion of the marrow compartment. Since the ends of bones are within joint capsules, such bone pain may not be readily associated with leukemic arthritis. In leukemic arthritis, however, effusion is a frequent accompaniment.

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[I3] Representative flow cytometric dot plots of the cells in synovial fluid from our patient illustrating A) CD45 (leukocyte common antigen) versus side scatter showing a predominance of CD45-positive cells; B) CD11b (myeloid cells) and CD15 (neutrophils, monocytes) co-expression on the leukemic cells; and, C) CD14 (monocytes) and CD13 (monocytes, neutrophils) expression with varying levels of maturation within the hematopoietic cells.


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cell clone in the synovium has been reported and may contribute to the resulting joint destruction.14 6. The gold standard for the diagnosis of leukemic arthritis is the demonstration of malignant cells in a synovial biopsy.9,15,16 However, as in this case, joint fluid analysis for leukemic cells is also invaluable.2,5,17-21 Indirect immunofluorescent assay (IFA) techniques utilizing monoclonal antibodies to leukemia cell antigens have also been used successfully.5,18-21 In addition, flow cytometry is considered by some to be more accurate than IFA methods because it provides a specific profile of leukemic cells and false negative synovial biopsies may be observed in cases with a patchy cellular infiltrate.5,17 Prior to considering leukemic arthritis as the cause of joint swelling in a patient with leukemia, infectious and crystalline forms of arthritis must be excluded. Moreover, serologic tests for antinuclear antibodies and rheumatoid factor are non-contributory and X-ray findings are non-specific.11 7. Nonsteroidal anti-inflammatory drugs (NSAIDs) can help alleviate the symptoms of leukemic arthritis.4,22 Intra-articular steroid injections have also been found to be safe and effective for alleviating symptoms in patients with osteoarthritis of the knee23; however, the value of intra-articular steroid injection for the relief of symptoms of leukemic arthritis has not been clearly established.5 Nevertheless, such treatment may be beneficial, since IL-1β mediated, or other immunologic mechanisms may play a role in the etiology of this disease. In addition, many patients respond to chemotherapy for their underlying disease,1,19 and radiation therapy has been useful in refractory cases.5 Patient’s Treatment and Course: Treatment of our patient with chemotherapy, intra-articular methylprednisolone acetate (Depo-Medrol) injection, and analgesics resulted in rapid resolution of his symptoms. Keywords: leukemic arthritis, crystal-induced arthritis, acute myelogenous leukemia, interleukin-1 beta 1. Costello PB, Brecher ML, Starr JI, et al. A prospective analysis of the frequency, course, and possible prognostic significance of the joint manifestations of childhood leukemia. J Rheumatol. 1983;10:753-757.

2. Luzar MJ, Sharma HM. Leukemia and arthritis: Including reports on light, immunofluorescent and electron microscopy of the synovium. J Rheumatol. 1983;10:132-135. 3. Isenberg DA, Shoenfeld Y. The rheumatologic complications of hematologic disorders. Semi Arth Rheum. 1983;12:348-358. 4. Silverstein MN, Kelly P. Leukemia with osteoarticular symptoms and signs. Ann Intern Med. 1963;59:637-645. 5. Evans TI, Nercessian BM, Sanders KM. Leukemic arthritis. Semin Arthritis Rheum. 1994;24:48-56. 6. Seda H, Alarcon GS. Musculoskeletal syndromes associated with malignancies. Curr Opin Rheumatol. 1995;7:48-53. 7. Seward BP. Lymphatic leukemia with severe pains in the joints. Med J Rec. 1930;131:444-446. 8. Cimaz R, Lippi A, Falcini F. Elbow arthritis: A rare inaugural manifestation of acute leukemia. Rev Rhum Engl Ed. 1999;66:520-522. 9. Spilberg I, Meyer GJ. The arthritis of leukemia. Arthritis Rheum. 1972;15:630635. 10. Thomas LB, Forkner CE, Frei E, et al. The skeleton lesions of acute leukemia. Cancer. 1961;14:608-621. 11. Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints. J Pediatr. 1999;134:53-57. 12. Taylor HG, Davis MJ, Hothersall TE. Hairy cell leukemia and rheumatoid arthritis. Br J Rheumatol. 1991;30:391-392. 13. Gagnerie F, Taillan B, Euller-Ziegler L, et al. Arthritis of the knees in B cell chronic lymphocytic leukemia: A patient with immunologic evidence of B lymphocytic synovial infiltration. Arthritis Rheum. 1988;31:815-816. 14. Rudwaleit M, Elias F, Humaljoki T, et al. Overexpanded B-cell clone mediating leukemic arthritis by abundant secretion of interleukin-1 beta: A case report. Arthritis Rheum. 1998;41:1695-1700. 15. Fort JG, Fernandez C, Jacobs SR, et al. B cell surface marker analysis of synovial fluid cells in a patient with monoarthritis and chronic lymphocytic leukemia. J Rheumatol. 1992;19:481-484. 16. Traycoff RB, Pascual E, Schumacher HR. Mononuclear cells in human synovial fluid. Identification of lymphoblasts in rheumatoid arthritis. Arthritis Rheum. 1976;19:743-748. 17. Sanders KM, Nercessian BM, Todd WM, et al. Leukemic arthritis diagnosed by flow cytometry of synovial fluid. J Rheumatol. 1993;20:1621. 18. Harden EA, Moore JO, Haynes BF. Leukemia-associated arthritis: Identification of leukemic cells in synovial fluid using monoclonal and polyclonal antibodies. Arthritis Rheum. 1984;27:1306-1308. 19. Schaller JG. Arthritis as a presenting manifestation of malignancy in children. J Pediatr. 1972;81:793-797. 20. Gramatzki M, Burmester GR, Konig HJ, et al. Synovial fluid involvement in null cell acute lymphoblastic leukemia diagnosed with monoclonal antibodies. J Rheumatol. 1988;15:500-504. 21. Fam AG, Voorneveld C, Robinson JB, et al. Synovial fluid immunocytology in the diagnosis of leukemic synovitis. J Rheumatol. 1991;18:293-296. 22. Weinberger A, Schumacher HR, Schimmer B, et al. Arthritis in acute leukemia. Clinical and histopathological observations. Arch Intern Med. 1981;141:11831187. 23. Raynauld JP, Buchland-Wright C, Ward R, et al. Safety and efficacy of longterm intra-articular steroid injection in osteoarthritis of the knee: A randomized double-blind, placebo-controlled trial. Arthritis Rheum. 2003;48:370-377.

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