Musculoskeletal pain and nonspecific symptoms are often the initial signs of cancer in about 20% of children who develop pediatric leukemia. Because of similar symptoms, childhood leukemia can masquerade as juvenile idiopathic arthritis, osteomyelitis, transient synovitis, or septic arthritis, resulting in delayed treatment.
What is leukemia?
Leukemia is a type of cancer that causes bone marrow to produce large numbers of abnormal white blood cells that enter the bloodstream and do not function properly. Leukemia accounts for 33-41% of all malignancies in children under 15 years of age with approximately 3250 children diagnosed each year in the United States.
Each type of leukemia is named for the blood cell that’s affected. The four most common types of leukemia are acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Acute lymphoblastic leukemia (ALL) represents about 75-85% of all cases of childhood leukemia and is the form which is known to mimic arthritis. Symptoms are often vague and nonspecific.
Common leukemia signs and symptoms include:
"¢ Fever or chills
"¢ Persistent fatigue, weakness
"¢ Frequent or severe infections
"¢ Losing weight without trying
"¢ Swollen lymph nodes, enlarged liver or spleen
"¢ Easy bleeding or bruising
"¢ Recurrent nosebleeds
"¢ Tiny red spots in your skin (petechiae)
"¢ Excessive sweating, especially at night
"¢ Bone pain or tenderness
"¢ Hematological abnormalities (anemia, low white blood cell count, low platelet count, circulating blasts)
How does leukemia look like juvenile arthritis?
Musculoskeletal symptoms are the primary complaint in 14% to 30% of pediatric ALL cases, sometimes before changes in peripheral blood are evident. Several case reports exist in the medical literature discussing patients who are initially (mis)diagnosed with juvenile idiopathic arthritis (JIA) due to bone pain and joint swelling, often in the lower extremities (ankle, knee, hip), to later be diagnosed with ALL. About 7% of children with ALL who initially have musculoskeletal manifestations meet diagnostic criteria for JIA.
Common signs and symptoms of juvenile idiopathic arthritis include:
"¢ Complaints of joint pain or abnormal joint use
"¢ Swollen joints, or limited motion, associated with pain, warmth, or redness
"¢ Joint stiffness, typically worse in the morning or after a nap
"¢ History of school absences or limited ability to participate in physical education classes
"¢ Persistent fatigue
"¢ Spiking fevers occurring once or twice each day at about the same time of day
"¢ Skin rash on the trunk and extremities lasting only a few hours
"¢ Psoriasis or more subtle dermatologic manifestations
"¢ Swollen lymph nodes, enlarged liver and spleen
"¢ Muscle tenderness, inflammation of tendons or ligaments
"¢ Inflammation of the eye, iritis or uveitis
"¢ Hematological abnormalities (elevated erythrocyte sedimentation rate or C-reactive protein, rheumatoid factor, antinuclear antibodies, high white blood cell count, high platelet count)
"¢ Radiographic abnormalities (soft tissue swelling, osteopenia and/or osteoporosis, joint-space narrowing, bony erosions, periosteitis, growth disturbances, synovial cysts)
What are the best ways to distinguish leukemia from arthritis in children?
Studies have identified three important features that predict a diagnosis of ALL and differentiate it from JIA, including:
"¢ Low white blood cell count (leukopenia)
"¢ Low-normal platelet count (thrombocytopenia)
"¢ Nocturnal pain
Children with leukemia often experience pain at night, non-articular bone pain, and joint pain that is out of proportion to physical signs and non-responsive to analgesics. Severe night pain - the kind that wakes you up from sleep - is seen more frequently in children with leukemia, while children with JIA usually describe achiness, stiffness, and a dull joint pain that is worse in the mornings. Dual enlargement of spleen and liver or swollen lymph nodes occur in 60% of ALL cases at presentation, however these can also be seen in arthritis patients.
Aside from musculoskeletal pain, children affected by ALL are at risk of several major secondary skeletal problems during and after treatment, such as osteonecrosis, reduced bone mineral density (BMD), osteoporosis and transient or permanent impairment of their growth. Common radiographic findings in adults with leukemia are osteopenia and osteolytic lesions, whereas osteosclerosis, osteolytic lesions, osteopenia, cortical and periosteal lesions, and metaphyseal radiolucent bands are common in children. "¨
Some diagnostic tests are less useful in differentiating between ALL and JIA. These include testing for the presence of antinuclear antibodies (ANA), rheumatoid factor, or increased levels of lactic dehydrogenase (LDH). In one study, levels of LDH were increased in 77% of leukemia patients (n=58), but also in 38% of patients with JIA (n=104). In the same study, approximately one third of patients with JIA were ANA-positive and of those children with leukemia who were tested (n=47), 17% were also ANA-positive (Jones, 2006).
Why should a child undergo bone marrow testing before taking steroids for arthritis symptoms?
With so much symptomatic overlap between pediatric leukemia patients who experience musculoskeletal complaints and patients who have juvenile arthritis, it is important to consider the possibility of leukemia in children with unexplained musculoskeletal pain. Peripheral blood tests and x-rays alone cannot be used to distinguish between ALL or JIA. Bone marrow examination should be performed to exclude leukemia, especially before a patient starts treatment with steroids or cytotoxic agents. Besides delaying appropriate treatment, these medications may mask underlying malignancy and reduce subsequent response to chemotherapy.
Chell J, Fernandes JA, Bell MJ. The orthopaedic presentation of acute leukaemia in childhood. Ann R Coll Surg Engl. 2001 May;83(3):186-189.
Gomoll AH. Childhood leukemia presenting as sternal osteomyelitis. Am J Orthop (Belle Mead NJ). 2007 Oct;36(10):E148-50.
Jones OY, Spencer CH, Bowyer SL, et al. A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis. Pediatrics. 2006 May;117(5):e840-4.
Kamel SR, Abdel-Nasser AM, Mohamed MM. Rheumatic manifestations of hematologic malignancies: Correlation with laboratory markers. J Hematol Malig. 2011 Dec;1(1):15-23. DOI:10.5430/jhm.v1n1p15.
Mulder H, Herregods N, Mondelaers V, Benoit Y, De Moerloose B. Musculoskeletal manifestations in children with acute lymphoblastic leukaemia. Belg J Hematol. 2012;3:3-11.
Murray MJ, Tang T, Ryder C, Mabin D, Nicholson JC. Childhood leukaemia masquerading as juvenile idiopathic arthritis. BMJ 2004 Oct;329(7472):959-961.
Onubogu UC, Okoh BAN, Eke G, Joboy-okei EA. Acute Lymphoblastic Leukaemia presenting as Juvenile Idiopathic Arthritis in a Nigerian boy. J Arthrit Rheum Res. 2013 Dec;1(1):9-11.
Rashid AKMM, Al Mamun A, Ahasan HAMN, Rasul CH. Leukemia mimicking juvenile rheumatoid arthritis. Pak J Med Sci. January-March 2005;21(1):85-87.
Sherry DD, Rabinovich CE, Poduval M. Juvenile Idiopathic Arthritis. Medscape.com (updated April 21, 2014). Accessed June 21, 2014 at http://emedicine.medscape.com/article/1007276
Tamashiro MS, Aikawa NE, Campos LMA, Cristofani LM, Odone-Filho V, Silva CA. Discrimination of acute lymphoblastic leukemia from systemic-onset juvenile idiopathic arthritis at disease onset. Clinics. 2011;66(10):1665-69.