Childhood leukaemia masquerading as juvenile idiopathic arthritis
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《英国医生杂志》
1 Addenbrooke's Hospital, Cambridge CB2 2QQ, 2 West Suffolk Hospital, Bury St Edmunds, Suffolk IP33 2QZ, 3 Birmingham Children's Hospital, Birmingham B4 6NH
Correspondence to: J C Nicholson james.nicholson@addenbrookes.nhs.uk
Introduction
Acute lymphoblastic leukaemia is the commonest childhood malignancy, with nearly 400 new cases each year in the United Kingdom. Initial presentation may involve the musculoskeletal system in up to two thirds of cases,3 and arthritis may be the only presenting feature of leukaemia.4 Consideration of other potential differential diagnoses when a child presents with unusual musculoskeletal symptoms may lead to earlier diagnosis of malignancy. Other reports have found similar diagnostic delay to our case, ranging from three to seven months.1
Barbosa et al showed that 62% of paediatric patients had musculoskeletal pain, but only 13% had clinical evidence of arthritis, at the onset of leukaemia; 8% of patients had been misdiagnosed with rheumatic fever or juvenile idiopathic arthritis before referral and some of these patients had already received steroids, delaying the start of appropriate treatment.3 However, differentiating rheumatic from malignant causes of musculoskeletal symptoms is difficult because early signs and symptoms are often similar. Comparing the histories of children with leukaemic arthritis and those with juvenile idiopathic arthritis, Ostrov et al showed that nocturnal pain, non-articular bone pain, and lack of joint stiffness were more often found in those with leukaemia.5 They also showed that although polyarticular involvement was more common in the juvenile idiopathic arthritis group, the leukaemic group more typically had painful pauci-articular arthritis. Cabral and Tucker also indicate that in those with leukaemia the clinical features are nearly always atypical for childhood rheumatic disease—for example, bone pain or tenderness that is non-articular in nature, especially if unilateral, should be regarded seriously.6
Tsai et al analysed results from patients initially diagnosed as having juvenile idiopathic arthritis in whom the diagnosis of acute lymphoblastic leukaemia was eventually made. They showed a lower white count and relative lymphocytosis on initial blood count compared with those who had a final diagnosis of juvenile idiopathic arthritis.7 Ostrov et al also showed that whereas neutrophilia was uniformly present in juvenile idiopathic arthritis, in acute lymphoblastic leukaemia a lymphocytosis predominated.5 From initial presentation until the week before the diagnosis of acute lymphoblastic leukaemia finally being made in our patient, the total white count (3.9-5.2x109/l) and neutrophil count (1.5-2.5x109/l) were always at the lower end of the reference range, with a relative lymphocytosis, correlating with these reports. Frank leucopenia and neutropenia did not appear until the week in which blasts became apparent on the peripheral blood film (table). Cabral et al compared similar groups and suggested that those with a normal or low platelet count at presentation were also more likely to have malignancy.8 Low or low normal counts suggest possible marrow infiltration and warrant further investigation, since an inflammatory process would be expected to result in raised counts. Serum lactate dehydrogenase is known to be a useful marker of cell turnover and is often raised in malignancy. Wallendal et al showed that although normal lactate dehydrogenase concentrations do not exclude malignancy, the presence of arthritis with raised lactate dehydrogenase and otherwise normal laboratory results is a cause for concern.9 Cabral et al, however, found that lactate dehydrogenase concentrations were raised in only 24% of patients who were subsequently diagnosed with acute lymphoblastic leukaemia,6 and Ostrov et al found no significant difference.5 Lactate dehydrogenase concentrations may not, therefore, be a reliable marker to distinguish juvenile idiopathic arthritis from acute lymphoblastic leukaemia.
Atypical features of juvenile idiopathic arthritis
Clinical
Predominantly nocturnal pain, may cause waking*
Degree of pain or systemic upset disproportionate to severity of arthritis*
Bony, non-articular pain or tenderness*
Pain requiring opiate analgesia*
Sequential improvement on initiation of steroid or cytotoxic treatment then subsequent rapid deterioration*
Asymmetrical pauciarticular pattern in presence of other atypical features
Laboratory
Severe anaemia
Low normal white cell and neutrophil count with relative lymphocytosis*
Thrombocytopenia
Increased serum lactate dehydrogenase concentrations
Acute phase response disproportionate to severity of arthritis
*Features present in our case.
Treatment with steroids is known to cause a left shift in the bone marrow and may cause difficulty in interpretation of aspirates. Révész et al showed that pre-treatment with steroids or other cytotoxic agents, such as methotrexate, may allow the malignant cells to develop resistance to these chemotherapeutic agents.2 Definitive treatment is more likely to be unsuccessful, with relapse of disease more common in these patients. Our experience is that about 15% of patients newly diagnosed with juvenile idiopathic arthritis receive either oral or intravenous steroid treatment of which only one quarter currently receive a bone marrow examination before starting treatment.
We therefore recommend that malignancy and, in particular, leukaemia must be considered in the initial differential diagnosis when a child presents with unexplained musculoskeletal symptoms. This caveat assumes even greater importance when the clinical or laboratory findings are atypical for juvenile idiopathic arthritis (box). Initially, however, the full blood count may well be normal or show only subtle changes and other markers such as erythrocyte sedimentation rate or lactate dehydrogenase are not reliable tests to differentiate malignancy from other diagnoses such as arthritis. Therefore we strongly advise that a paediatric rheumatologist should be involved early in the assessment of children with arthritis and a bone marrow examination should be done in atypical cases, certainly before commencing steroids or other cytotoxic agents.
Leukaemia must be excluded in juvenile arthritis before starting steroids or cytotoxic agents
Contributors: TT had the original idea. TT and MJM wrote the paper and searched for references. MJM revised the manuscript. CR, DM, and JCN cared for the patient and wrote and revised the manuscript. JCN is guarantor.
Funding: None.
Competing interests: None declared.
Ethical approval: Not needed.
References
Bradlow A, Barton C. Arthritic presentation of childhood leukaemia. Postgrad Med J 1991;67: 562-4.
Révész T, Kardos G, Kajtár P, Schuler D. The adverse effect of prolonged prednisolone pretreatment in children with acute lymphoblastic leukaemia. Cancer 1985;55: 1637-40.
Barbosa CM, Nakamura C, Terreri MT, Lee ML, Petrilli AS, Hilário MO. Musculoskeletal manifestations at the onset of acute leukaemias in childhood. J Pediatr (Rio J) 2002;78: 481-4.
Jonsson OG, Sartain P, Ducore JM, Buchanan GR. Bone pain as an initial symptom of childhood acute lymphoblastic leukaemia: association with nearly normal haematologic indexes. J Pediatr 1990;117: 233-7.
Ostrov BE, Goldsmith DP, Athreya BH. Differentiation of systemic juvenile rheumatoid arthritis from acute leukaemia near the onset of disease. J Pediatr 1993;122: 595-8.
Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints. J Pediatr 1999;134: 53-7.
Tsai MJ, Yan DC, Chiang BL, Chou CC, Hsieh KH, Lin KH. Childhood leukaemia mimicking juvenile rheumatoid arthritis. Acta Paed Sin 1995;36: 274-8.
Cabral DA, Malleson PN, Petty RE. Spondyloarthropathies of childhood (review). Pediatr Clin North Am 1995;42: 1051-70.
Wallendal M, Stork L, Hollister JR. The discriminating value of serum lactate dehydrogenase levels in children with malignant neoplasms presenting as joint pain. Arch Pediatr Adolesc Med 1996;150: 70-3.(M J Murray, specialist re)
Correspondence to: J C Nicholson james.nicholson@addenbrookes.nhs.uk
Introduction
Acute lymphoblastic leukaemia is the commonest childhood malignancy, with nearly 400 new cases each year in the United Kingdom. Initial presentation may involve the musculoskeletal system in up to two thirds of cases,3 and arthritis may be the only presenting feature of leukaemia.4 Consideration of other potential differential diagnoses when a child presents with unusual musculoskeletal symptoms may lead to earlier diagnosis of malignancy. Other reports have found similar diagnostic delay to our case, ranging from three to seven months.1
Barbosa et al showed that 62% of paediatric patients had musculoskeletal pain, but only 13% had clinical evidence of arthritis, at the onset of leukaemia; 8% of patients had been misdiagnosed with rheumatic fever or juvenile idiopathic arthritis before referral and some of these patients had already received steroids, delaying the start of appropriate treatment.3 However, differentiating rheumatic from malignant causes of musculoskeletal symptoms is difficult because early signs and symptoms are often similar. Comparing the histories of children with leukaemic arthritis and those with juvenile idiopathic arthritis, Ostrov et al showed that nocturnal pain, non-articular bone pain, and lack of joint stiffness were more often found in those with leukaemia.5 They also showed that although polyarticular involvement was more common in the juvenile idiopathic arthritis group, the leukaemic group more typically had painful pauci-articular arthritis. Cabral and Tucker also indicate that in those with leukaemia the clinical features are nearly always atypical for childhood rheumatic disease—for example, bone pain or tenderness that is non-articular in nature, especially if unilateral, should be regarded seriously.6
Tsai et al analysed results from patients initially diagnosed as having juvenile idiopathic arthritis in whom the diagnosis of acute lymphoblastic leukaemia was eventually made. They showed a lower white count and relative lymphocytosis on initial blood count compared with those who had a final diagnosis of juvenile idiopathic arthritis.7 Ostrov et al also showed that whereas neutrophilia was uniformly present in juvenile idiopathic arthritis, in acute lymphoblastic leukaemia a lymphocytosis predominated.5 From initial presentation until the week before the diagnosis of acute lymphoblastic leukaemia finally being made in our patient, the total white count (3.9-5.2x109/l) and neutrophil count (1.5-2.5x109/l) were always at the lower end of the reference range, with a relative lymphocytosis, correlating with these reports. Frank leucopenia and neutropenia did not appear until the week in which blasts became apparent on the peripheral blood film (table). Cabral et al compared similar groups and suggested that those with a normal or low platelet count at presentation were also more likely to have malignancy.8 Low or low normal counts suggest possible marrow infiltration and warrant further investigation, since an inflammatory process would be expected to result in raised counts. Serum lactate dehydrogenase is known to be a useful marker of cell turnover and is often raised in malignancy. Wallendal et al showed that although normal lactate dehydrogenase concentrations do not exclude malignancy, the presence of arthritis with raised lactate dehydrogenase and otherwise normal laboratory results is a cause for concern.9 Cabral et al, however, found that lactate dehydrogenase concentrations were raised in only 24% of patients who were subsequently diagnosed with acute lymphoblastic leukaemia,6 and Ostrov et al found no significant difference.5 Lactate dehydrogenase concentrations may not, therefore, be a reliable marker to distinguish juvenile idiopathic arthritis from acute lymphoblastic leukaemia.
Atypical features of juvenile idiopathic arthritis
Clinical
Predominantly nocturnal pain, may cause waking*
Degree of pain or systemic upset disproportionate to severity of arthritis*
Bony, non-articular pain or tenderness*
Pain requiring opiate analgesia*
Sequential improvement on initiation of steroid or cytotoxic treatment then subsequent rapid deterioration*
Asymmetrical pauciarticular pattern in presence of other atypical features
Laboratory
Severe anaemia
Low normal white cell and neutrophil count with relative lymphocytosis*
Thrombocytopenia
Increased serum lactate dehydrogenase concentrations
Acute phase response disproportionate to severity of arthritis
*Features present in our case.
Treatment with steroids is known to cause a left shift in the bone marrow and may cause difficulty in interpretation of aspirates. Révész et al showed that pre-treatment with steroids or other cytotoxic agents, such as methotrexate, may allow the malignant cells to develop resistance to these chemotherapeutic agents.2 Definitive treatment is more likely to be unsuccessful, with relapse of disease more common in these patients. Our experience is that about 15% of patients newly diagnosed with juvenile idiopathic arthritis receive either oral or intravenous steroid treatment of which only one quarter currently receive a bone marrow examination before starting treatment.
We therefore recommend that malignancy and, in particular, leukaemia must be considered in the initial differential diagnosis when a child presents with unexplained musculoskeletal symptoms. This caveat assumes even greater importance when the clinical or laboratory findings are atypical for juvenile idiopathic arthritis (box). Initially, however, the full blood count may well be normal or show only subtle changes and other markers such as erythrocyte sedimentation rate or lactate dehydrogenase are not reliable tests to differentiate malignancy from other diagnoses such as arthritis. Therefore we strongly advise that a paediatric rheumatologist should be involved early in the assessment of children with arthritis and a bone marrow examination should be done in atypical cases, certainly before commencing steroids or other cytotoxic agents.
Leukaemia must be excluded in juvenile arthritis before starting steroids or cytotoxic agents
Contributors: TT had the original idea. TT and MJM wrote the paper and searched for references. MJM revised the manuscript. CR, DM, and JCN cared for the patient and wrote and revised the manuscript. JCN is guarantor.
Funding: None.
Competing interests: None declared.
Ethical approval: Not needed.
References
Bradlow A, Barton C. Arthritic presentation of childhood leukaemia. Postgrad Med J 1991;67: 562-4.
Révész T, Kardos G, Kajtár P, Schuler D. The adverse effect of prolonged prednisolone pretreatment in children with acute lymphoblastic leukaemia. Cancer 1985;55: 1637-40.
Barbosa CM, Nakamura C, Terreri MT, Lee ML, Petrilli AS, Hilário MO. Musculoskeletal manifestations at the onset of acute leukaemias in childhood. J Pediatr (Rio J) 2002;78: 481-4.
Jonsson OG, Sartain P, Ducore JM, Buchanan GR. Bone pain as an initial symptom of childhood acute lymphoblastic leukaemia: association with nearly normal haematologic indexes. J Pediatr 1990;117: 233-7.
Ostrov BE, Goldsmith DP, Athreya BH. Differentiation of systemic juvenile rheumatoid arthritis from acute leukaemia near the onset of disease. J Pediatr 1993;122: 595-8.
Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints. J Pediatr 1999;134: 53-7.
Tsai MJ, Yan DC, Chiang BL, Chou CC, Hsieh KH, Lin KH. Childhood leukaemia mimicking juvenile rheumatoid arthritis. Acta Paed Sin 1995;36: 274-8.
Cabral DA, Malleson PN, Petty RE. Spondyloarthropathies of childhood (review). Pediatr Clin North Am 1995;42: 1051-70.
Wallendal M, Stork L, Hollister JR. The discriminating value of serum lactate dehydrogenase levels in children with malignant neoplasms presenting as joint pain. Arch Pediatr Adolesc Med 1996;150: 70-3.(M J Murray, specialist re)