Musculoskeletal pain is a frequent complaint among children but only in few cases it implies severe diseases such as malignancies or chronic inflammatory diseases. Only in very few cases musculoskeletal pain is an isolated sign hindering the formulation of the diagnosis. In some of those cases general practitioners or paediatricians address the patient to the rheumatologist or the orthopaedist who tend to consider musculoskeletal symptoms as a sign of a chronic inflammatory disease. Therefore they prescribe analyses in order to validate their clinical hypothesis or start treatment without a clear diagnosis. In such a case, treatment with corticosteroids relieves symptoms thus causing a further delay in the diagnosis. Even when both diagnostic hypotheses are included, it can be hard to distinguish the clinical signs of JIA from malignancies because symptoms at the onset may be the same [3, 9]. Moreover, in the absence of pathognomonic test the diagnosis of JIA requires the exclusion of all the other causes of musculoskeletal pain. Furthermore, when no haematological signs are present, even leukaemia or a tumour could be difficult to detect. This clinical overlapping explains the need to always exclude a malignancy in children with musculoskeletal symptoms, especially when the clinical pattern is not characteristic of a specific rheumatic disease and/or in the presence of organomegaly or abnormal laboratory or imaging data.
A limited number of studies have been conducted in order to examine the value of diagnostic markers in the differential diagnosis between JIA and malignancies in children [7–9] and results are often inconsistent. In order to identify early parameters useful for a differential diagnosis, clearly defining the role of laboratory tests in terms of usage within the clinical diagnostic algorithms and the patient population for whom they are intended, in the present study we retrospectively evaluated ten-years data of two different groups of children with musculoskeletal pain, one affected by tumour and the other by JIA. No significant difference was found between the two groups for sex and age at the time of the diagnosis. High C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were not relevant parameters, being CRP slightly higher among the JIA group, but with no statistically significant difference. Some authors suggest taking the neutrophil count carefully into consideration in a child complaining musculoskeletal pain [2, 9]. Our results confirm a statistically significant difference in the neutrophil count between the two groups, being lower values significantly most frequent among patients with tumour (45.5% vs 3.3%) or leukaemia (52.5%), with high specificity, PPV and LR+, but low sensitivity. This means that a normal result of this test is very frequent among “non tumour” patients even though an altered result is not a clear sign of a “tumour/leukaemia” patient.
The same results were obtained for the haemoglobin levels: anaemia (i.e. Hb <10 g/dl) was more frequently found in the tumour group (56.7% vs 8.8%) or in the leukaemia group (57.8%) with a statistically significant difference. However, it has been reported that anaemia from chronic illness does occur in children with JIA and, for this parameter, we found low sensitivity (56.7%) for tumours. An abnormal platelet count was observed in both groups of patients, with lower values among the tumour group and higher values among the JIA group (p <0.05).
According to literature, high LDH level proved a useful predictive factor for tumours: abnormal values were more prevalent among the tumour group (87.9% vs 67.3%; sensitivity 88.0%). In fact, as previously reported in ALL patients , a twofold or even higher increase was found exclusively among children with malignancies. Consequently, if a child complains musculoskeletal pain, high LDH level should be considered suspicious and it requires further analyses to exclude a malignancy.
Moreover, in the comparison between the patients with tumour and those with JIA, the combination of all three abnormal values in neutrophil count, Hb and LDH increased sensitivity and specificity.
We also investigated clinical parameters like fever and lymphadenopathy which resulted significantly more frequent in patients with tumour despite a high number of missing data. However, previous papers have already reported the limited value of these clinical parameters for the comparison of ALL and JIA [9–11].
Some diagnostic tests such as ANA and complement have been reported as not meaningful to differentiate tumours and JIA . In our study the frequency of positive ANA patients was higher among the JIA group and the difference was statistically significant, but this test was characterized by low sensitivity and low specificity. No significant difference in the other screened auto-antibodies appeared between the two groups. Furthermore, no significant difference was detected in the immunoglobulin profile even though we found abnormal IgA values more frequently among the tumour group and this result was statistically significant with high specificity.
An odd result, seemingly difficult to comment, concerns a positive anti-CMV IgG titre found more frequently among patients with tumours than among JIA patients, with a statistically significant difference and with high specificity and high sensitivity, high PPV and low NPV. Our data showed that the presence of these antibodies is the most valid feature in patients with tumour or leukaemia versus patients with JIA, although the low number of tests taken in JIA patients makes the numbers less reliable. Indeed, it has been reported that leukemic patients have a higher titre of antibodies against many herpes viruses than the healthy population [12, 13].