Early in the disease course, the patient showed relatively minor symptoms in the form of knee pain that rapidly resolved, and pain in the right foot that was initially attributed to a trauma. Haematological status and a plain radiograph of the foot were both normal, and the boy was therefore treated symptomatically without any underlying condition being diagnosed. Four months after symptom onset, the boy began to have difficulty bearing weight on his foot. This is a red flag, but unfortunately no additional diagnostic testing was performed. After a further month of increasing pain upon walking and eventually also nocturnal pain, another radiograph was obtained. This triggered the testing that led ultimately to the correct diagnosis. This case report is thus an example of a workup involving professionals from many different disciplines in both the primary and specialist healthcare services, but where a lack of communication and oversight may have resulted in a delayed diagnosis.
Acute leukaemia is the most common cancer in children (0–18 years). There were 44 new cases in Norway in 2020, of which 80 % were acute lymphoblastic leukaemia (2). With modern treatment protocols, the prognosis in children is good with five-year survival of up to 94 % (1). The diagnosis is made upon establishing that > 25 % of cells in the bone marrow are immature B or T lymphoblasts (1, 3). The typical symptoms of leukaemia result from involvement of different haematological cell lines: increased bleeding tendency or cutaneous haematomas due to thrombocytopenia; pallor and fatigue due to anaemia; and fever and increased vulnerability to infection due to neutropenia (4). Extramedullary involvement can give rise to palpable leukaemic infiltrates in organs including the skin, testicles, and lymph nodes. Musculoskeletal symptoms are common in leukaemia and occur in up to one third of patients, most often in cases of B-cell acute lymphoblastic leukaemia (5, 6). These symptoms can be challenging to diagnose, as they often occur in isolation (7). A retrospective analysis of 783 children with acute lymphoblastic leukaemia found that those presenting with musculoskeletal symptoms were more likely to have normal leukocyte, platelet, and haemoglobin levels, and less likely to have hepatomegaly or splenomegaly (5). As a result, their symptoms are often viewed as being of orthopaedic or rheumatological origin (8). Delayed diagnosis does not seem to affect the prognosis, however, possibly because these individuals tend to have less aggressive forms of the disease (5, 7).
Our case report is an example of a leukaemia that manifested with sparse musculoskeletal symptoms, and where further diagnostic testing revealed few additional signs and symptoms. Nevertheless, studies have shown that certain signs and symptoms are positive predictors for a diagnosis of acute lymphoblastic leukaemia in children with bone pain. A retrospective multicentre study of 277 children who received a diagnosis of either acute lymphoblastic leukaemia or juvenile rheumatoid arthritis found that nocturnal pain, a low leukocyte count (<4 × 109/L), low-to-normal platelet levels (150–250 × 109/L), and low haemoglobin levels (<11 g/dL) were positive predictors of acute lymphoblastic leukaemia (9), with the combination of low leukocyte count, low-to-normal platelets and nocturnal pain having a sensitivity of 100 % and a specificity of 85 % for this diagnosis. Antinuclear antibodies (ANA), rash and objective signs of arthritis are not useful in differentiating between leukaemia and juvenile arthritis (9).
Ultrasound and MRI scans are currently considered the best imaging modalities for evaluating suspected juvenile arthritis (10). Plain radiography is less precise but can be useful when evaluating differential diagnoses. It can also help identify leukaemia in patients presenting with bone pain, even when the findings are subtle (11). The presence of lucent metaphyseal bands, osteolysis, a periosteal reaction or osteosclerosis had a sensitivity of 90.0 % and specificity of 99.8 % for a leukaemia diagnosis (11). Our patient's first radiograph was normal, as was his haematological status. When his symptoms worsened and he began to experience weight-bearing pain four months later, unfortunately no further diagnostic imaging was performed. In retrospect, another X-ray or MRI scan could have been considered as soon as this red flag was identified.
The presence of leukaemic infiltrates in the testicles and under the eyes could also have allowed the diagnosis to be made earlier. The boy reported a painless scrotal swelling just over two months before he was diagnosed. Although this is in principle a red flag, it was probably assigned less importance because two ultrasound scans had shown normal-sized testicles and an enlarged epididymis; findings that were confirmed during surgery. Scrotal swelling is a rare early symptom of leukaemia, with one study reporting its presence in only 1.9 % of boys under 15 years of age (12). Cutaneous leukaemic infiltrates are also an infrequent early manifestation of acute leukaemia and are most often associated with acute myeloid leukaemia (AML) (13). In our patient, the cutaneous infiltrates were noticed only a few days before the diagnosis was made.
Although acute paediatric leukaemia often presents with atypical symptoms, the disorder is usually characterised by a constellation of multiple signs and symptoms or abnormal blood cell counts. Musculoskeletal symptoms, however, tend to occur in isolation. Leukaemia should therefore be considered as a differential diagnosis in patients with musculoskeletal symptoms, especially if any red flags are present. It is also important to examine the testicles when clinically indicated in boys. Testicular swelling should always be considered pathological, and the cause investigated. There should be a low threshold for additional diagnostic testing, including blood tests, radiography and ultrasound, in cases of unexplained skeletal pain and scrotal swelling. In most cases the results will raise suspicion of leukaemia as the underlying diagnosis.