Acute lymphobiastic leukaemia (ALL) usually presents with signs of bone marrow failure, Occasionally ALL in children may present with non-specific or misleading clinical features. In a retrospect analysis of 25 consecutive cases of childhood ALL, we identified three children who were initially managed and discharged as acute osteomyelitis, juvenile chronic arthritis and postinfectious arthralgia respectively. They had mild normochromic, normocytic anaemia and two had transient leucopenia. Their platelet counts were normal and none had circulating blasts. The severity of their skeletal symptoms was out of proportion to the clinical and radiological finding. They failed to respond to the initial management and diagnosis was delayed for an average of 42 days and eventually confirmed on the marrow aspirate. Complete remission was attained in all cases with standard chemotherapy and had been maintained for an average of 29 months. ALL should be considered as a differential diagnosis in children complaining of multiple or persistent joint pains, especially in the presence of atypical clinical features or poor response to treatment.published_or_final_versio

Chan, GCF

Chiu, W

Lau, YL

Lee, ACW

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Title Childhood acute lymphoblastic leukaemia masquerading asprimary skeletal problemAuthor(s) Lee, ACW; Chan, GCF; Chiu, W; Lau, YLCitation Journal of the Hong Kong Medical Association, 1994, v. 46 n. 3,p. 231-235Issued Date 1994URL http://hdl.handle.net/10722/53445Rights Journal of the Hong Kong Medical Association. Copyright ©Hong Kong Medical Association.Anselm C. W. Lee, Godfrey C. F. Chan, W. Chiu, and Y. L. LauAbstractAcute lymphobiastic leukaemia (ALL) usually presents with signs of bone marrow failure,Occasionally ALL in children may present with non-specific or misleading clinical features. In aretrospect analysis of 25 consecutive cases of childhood ALL, we identified three children whowere initially managed and discharged as acute osteomyelitis, juvenile chronic arthritis and post-infectious arthralgia respectively. They had mild normochromic, normocytic anaemia and twohad transient leucopenia. Their platelet counts were normal and none had circulating blasts. Theseverity of their skeletal symptoms was out of proportion to the clinical and radiological finding.They failed to respond to the initial management and diagnosis was delayed for an average of 42days and eventually confirmed on the marrow aspirate. Complete remission was attained in allcases with standard chemotherapy and had been maintained for an average of 29 months. ALLshould be considered as a differential diagnosis in children complaining of multiple or persistentjoint pains, especially in the presence of atypical clinical features or poor response to treatmentKeywords: Acute lymphobiastic leukaemia; Children; Skeletal complication.IntroductionAcute lymphobiastic leukaemia (ALL) is the com-monest childhood malignancy both in Hong Kong1and elsewhere.2 It represents 30% of all children un-dergoing cancer treatment in the Department ofPaediatrics, Queen Mary Hospital, between 1986 and.1992. The typical child presents with signs and symp-toms of pancytopenia such as bleeding, anaemia andinfectious manifestations.3 Atypical presentation, suchas orthopaedic or rheumatoid features, is not uncom-mon and could be mistaken as the primary diagnosis.4The presence of a normal or near-normal blood count,with or without anti-nuclear factor (ANF), could fur-ther complicate the diagnosis.5 A retrospective analysisDepartment of Paediatrics, the University of Hong Kong, Queen MaryHospital, Pokfulam, Hong KongAnselm C. W. Lee, MB, BS, MRCP(UK)Godfrey C. F. Chan, MD, MRCP(UK)W. Chiu, MB, BS, MRCP(UK)Y. L. Lau, MD, FRCP(Edin)Correspondence to: Dr Anselm C. W. Leeis undertaken to assess the local prevalence of thispresentation and identify factors which could promptto the correct diagnosis.Materials and methodsAll children under the age of 12 years presented tothe Children Haematology and Oncology Service(CHAOS), Department of Paediatrics, Queen MaryHospital, with a diagnosis of ALL between January1989 and December 1.992 were included for study.Patients were noted for their first diagnosis upondischarge, as well as their demographic data, haema-toiogical and biochemical findings, leukaemiccytoimmunohistochemical analysis/and treatmentoutcomes.Patients first discharged with a diagnosis otherthan ALL after complete physical examination and aminimal investigations of complete blood counts withdifferentials, blood biochemistry and. relevant radio-logical investigations, were studied in detail (the studycases). Follow-up and survival are calculated from231232 J Hong Kong Med Assoc Vol. 46, No. 3, September 1994the date of diagnosis to 31 December 1993 or to thedate of death where appropriate. Relapse-free sur-vival is calculated from the date of first completeremission to the date of relapse, date of death or 31December 1993, whichever is earlier. Study cases arecompared with other cases diagnosed in the sameperiod of study in terms of age at diagnosis, follow-up and haematological indices at the time of diagnosis.The two sample Student's t test using the Instat™(GraphPad™, San Diego, U.S.A.) is applied whereappropriate.ResultsA total of 26 cases of ALL were diagnosed during thestudy period. These include 25 Chinese children andone Caucasian boy. One child with Burkitt's leukae-mia was excluded from further analysis as the diseaseis clinically distinct and requires different manage-ment. The mean age of the remaining 25 patients was4.9 years (range 0.4 to 11.7) and the male:female ratiowas 2.6 (18 boys:7 girls). Children were treated with amodified protocol from the American Children Can-cer Study Group6 before 1991, while others diagnosedin and after 1991 were treated with the United King-dom Acute Lymphoblastic Leukaemia protocol.7 Twopatients were further excluded for analysis of survivalbecause of transferral and repatriation to other centresfor treatment. Twenty (87%) were surviving of which18 (78%) remained in the first complete remission fora mean duration of 30 months (range 16 to 57 months).Five patients relapsed and three died at 14, 16, and 36months respectively after diagnosis, including onepatient with infantile ALL and one with Philadel-phia-chromosome positive ALL.Twenty-two cases had a straight forward diagno-sis of ALL with manifestations of pancytopenia andorganomegaly soon after admission. Three patients(12.0%), however, were initially managed differentlyupon the first discharge. They were treated as acuteosteomyelitis, juvenile chronic arthritis and post-in-fectious arthralgia respectively. Despite the absenceof circulating blasts, the diagnosis of ALL was madewith bone marrow aspirations. With appropriatechemotherapy, they all remained in the first completeremission for 20, 24 and 42 months respectively.Compared with other children, they were similar interms of age and duration of follow-up. A signifi-cantly higher presenting haemoglobin level andplatelet count was evident, and a tendency towards alow and normal leucocyte count was also seen (Table1). The case histories of these three patients are asfollows and their relevant laboratory findings werelisted in Table 2.Case lA five-year-old boy complained of backache and lefthip pain and refused to walk. There was no history oftrauma. He had a fever of 39.4°C but no obvious focusof infection. There was no lymphadenopathy orhepatosplenomegaly. The left hip was held in abduc-tion and external rotation while adduction and internalrotation was limited by pain. Examination of the backwas normal. Initial investigations showed a mildnormochromic, normocytic anaemia (haemoglobin10.2 g/dl) and a white cell count of 2.2 x 109/1. Theerythrocyte sedimentation rate (ESR) was 60 mm inthe first hour. Blood biochemistries were normal andrepeated blood cultures were negative. On plain ra-diograph, the spine and the pelvic bones were normal.There was a small lucency seen in the proximalmetaphysis of the left femur.99 Tc-bone scan, how-ever, showed an increased uptake over the left hipjoint but not the metaphysis. Bone marrow aspirationfrom the posterior iliac crest revealed normalhaemopoiesis without malignant infiltration.The child was therefore managed as a case of acuteosteomyelitis with a combination of ampicillin, cloxa-cillin and fusidic acid for a duration of six weeks. Thetemperature subsided but the child still complainedof intermittent left hip pain. A repeat bone scan aftercompletion of antibiotic treatment showed normaluptake in the left hip region. There was, however, anincreased uptake in the left 11th rib. Repeat bloodTable 1. A comparison of the haematological indices between the study and other casesStudy cases (n=3)Mean ± SDOther cases (n=22)Mean ± SD p valueAge (years)Follow-up (months)Haemoglobin (g/dl)White cell count (x109/l)Platelet count (x109/l)4.0 + 0.730 + 910.0 + 0.54.6 ±1.2243 + 615.0 ±3.231 +14*7.4 + 1.648.9 + 66.275 ±69NSNS0.01NS0.0006* Excluding 2 children who have been transferred to other centres.NS = Non significantLee et al.: Childhood ALL presenting as skeletal problem 233Table 2. The clinical and laboratory features of the three study casesSex/AgeClinical jointinvolvemenInitial diagnosisDay of investigation*Hgb (g/dl)WCC (x 109/l)— neutrophils— lymphocytesePlatelets (x 109/l)ESR (mm/hour)Calcium (mmol/l)P04 (mmol/l)ALP (u/l)ALT (u/l)Bilirubin (umol/l)LDH (u/l)Antinuclear factorRFCase 1M/5Left hipLumbar spineOsteomyelitis-50 010.2 10.32.2 4.00.72 1.081.41 2.80413 29560 1352.451.501644216472NDNDCase 2F/3Right shoulderCervical spineElbows, kneesJuvenile chronic arthritis-45 010.2 10.66.8 6.02.79 2.223.88 3.00446 198ND 1272.521.76172467702— —Case 3M/4Left kneePost-infection arthralgia-14 09.0 9.63.6 4.051.91 2.381.58 1.38285 36566 952.441.7314074473+ NDND* Day O denotes the day of diagnostic bone marrow examination.Abbreviations: ALT = alanine transferase; ALP = alkaline phosphatase;Hgb = haemoglobin; LDH = lactate dehydrogenase;PO4= phosphate; RF = rheumatoid factor;+ = positive; - = negative.ESR = erythrocyte sedimentation rate;ND = not done;WCC = white cell count;counts and biochemistries showed essentially the samefindings as before. Bone marrow aspiration was re-peated nine weeks after initial presentation, whichconfirmed the diagnosis of common ALL.Case 2A three-year-old girl complained of fever and rightshoulder and neck pain limiting movements for oneweek. A viral respiratory illness was diagnosed byher family doctor and symptomatic treatment resultedin subsidence of temperature but not the joint pains.Clinical examination and plain radiographs of thecervical spine and right shoulder joint, however, werenormal. Investigations showed only a mild normo-chromic, normocytic anaemia (haemoglobin 10.2 g/dl) while other haematological and biochemical testswere normal. Her symptoms waxed and waned foranother five weeks and the elbows and knees becameinvolved before she was re-admitted with a fever of38.5°C. Examination then found a miserable child withan enlarged liver of 3 cm below the costal margin.Repeat serological markers, blood counts andbiochemistries, and X-rays were normal. The ESR was127 mm/hour. She was put on aspirin with a provi-sional diagnosis of juvenile chronic arthritis (JCA),but no response was seen after the first week of treat-ment. A bone marrow aspiration performed six weeksafter initial presentation confirmed the diagnosis ofcommon ALL.Case 3A four-year-old boy complained of on and off fever-associated left knee pain for a duration of one month.A mild pharyngitis was found and the rest of theclinical examination including joints were normal.Initial investigation showed only a mild normochro-mic, normocytic anaemia of haemoglobin 9.0 g/dl.The ESR was 66 mm/hour and the ANF was positiveat 1:40. The anti-DNA antibody and rheumatoid factorwere negative. The fever and joint symptoms re-sponded to oral penicillin therapy and the child wasdischarged with a diagnosis of post-infectiousarthralgia. However, he was re-admitted ten dayslater with resurgence of symptoms and fever. Blood234 J Hong Kong Med Assoc Vol. 46, No. 3, September 1994counts and biochemistries remained essentially thesame. X-ray of the left knee remained normal but askeletal survey showed a suspicious osteolytic lesionover the right femoral head. A bone marrow aspira-tion was performed which revealed a diagnosis ofcommon ALL two weeks after the initial presenta-tion.DiscussionAcute lymphoblastic leukaemia in children is now acurable disease, with a long term remission rate ap-proaching 70%.3 Although the majority of childhoodALL present with signs and symptoms ofpancytopenia, an occasional child may complain ofatypical features. Skeletal complaints are common atdiagnosis, but could be the sole or predominant clini-cal feature occasionally.8 Where patients present witha normal or near-normal blood count without detect-able circulating blasts, the diagnosis could be mistakenas a primary skeletal problem.9 Positive serological testto ANF, as in Case 3, could add further confusion.5Several clinical and laboratory features may lend cluesto the underlying diagnosis.ALL and juvenile chronic arthritis share a numberof common clinical features, such as fever, joint pains,and signs of organomegaly.10 The pattern of joint in-volvement tends to be pauci-articular and affects thelower limbs more often in ALL.11, 12 Children with ALLoften have symptoms that are out of proportion to theclinical findings.9 In this series, we also noted that theradiological features did not correspond to the clini-cal features, such as the finding of a normal X-ray(Cases 2 and 3), or the presence of a lesion distant tothe clinically involved site (Cases 1 and 3). RaisedESR could be found in leukaemia, JCA and skeletalinfections. The presence of a high ESR, however,should alert the possibility of leukaemia when theskeletal X-rays are normal.13Haematological findings could be deceptive as il-lustrated by our three cases. Normochromic,normocytic anaemia is fairly non-specific and couldbe present in any children with chronic illness orinfections. It has been noted that children with JCArarely become leukopenic or thrombocytopenic.9 Avigorous search for circulating blast should be at-tempted in each case, but it is absent in up to one-thirdof such cases.5 Bone marrow aspiration may have tobe repeated before the diagnosis becomes apparent12as in Case 1.Children with multiple or persistent bone or jointpains should be followed up for at least five months.9The emergence of atypical features or failure of re-sponding to standard treatment should prompt thesearch for an underlying malignancy. It is importantfor clinician dealing with such children not to insti-tute steroid treatment empirically. Steroid therapynot only blurs the distinction between ALL and rheu-matoid disorders, but also makes subsequentlaboratory investigations difficult. Children with ALLoften respond partially to steroid treatment alone,but subsequent relapse is inevitable with a much worseprognosis.14Finally, it is interesting to see that, provided thesechildren are managed with the appropriate anti-leu-kaemic treatment, their prognosis is comparable toother leukaemic children despite the initial delay indiagnosis as illustrated in our cases. Common ALLappears to be the phenotype associated with suchpresentation but the available literature does not con-tain enough studied cases to confirm the association.AcknowledgementsThe authors would like to thank Dr L. C. Chan andhis staff of the Haematology Unit, Department ofPathology, Dr F. L. Chan and his staff, Department ofDiagnostic Radiology, Queen Mary Hospital, for theirexcellent aid in diagnosis, and the nursing staff, De-partment of Paediatrics, Queen Mary Hospital, fortheir high standard of supportive care. We also thankthe various physicians for their kind referral.References1 Hospital Authority. Hong Kong Cancer Registry: 1989annual statistical report. Hong Kong: GovernmentPrinter, 1993: 25-8.2. Riehm H, Feickert HJ, Lampert F. Acute lymphoblasticleukaemia. In: Voute PA, Barrett A, Bloom HJG, Le-merle J, Neidhardt MK, eds. Cancer in children. Berlin:Springer-Verlag, 1986: 101-8.3. Poplack DG. Acute lymphoblastic leukemia. In: PizzoPA, Poplack DG, eds. Principles and practice of pediat-ric oncology. Philadelphia: Lippincott, 1989: 323-66.4. Spilberg I, Meyer GJ. The arthritis of leukemia. Arthri-tis Rheum 1972; 15: 630-5.5. Jonsson OG, Sartain P, Ducore JM, Buchanan GR. Bonepain as an initial symptom of childhood acute lym-phoblastic leukemia: association with nearly normalhematologic indexes. J Pediatr 1990; 117: 233-7.6. Gaynon PS, Bleyer WA, Steinherz PG, et al. ModifiedBFM therapy for children with previously untreatedacute lymphoblastic leukemia and unfavorable prog-nostic features. Report of Children's Cancer StudyGroup Study CCG-193P. Am J Pediatr Hematol Oncol1988; 10: 42-50.7. Medical Research Council Working Party on Leukae-mia in Children. Acute lymphoblastic leukaemia trialUKALL XI children. United Kingdom: Medical Re-search Council, 1990.8. Gallagher D, Heinrich SD, Craver R, Ward K, WarrierR. Skeletal manifestations of acute lymphoblasticleukemia in childhood. Orthopedics 1991; 14: 485-92.Lee et al.: Childhood ALL presenting as skeletal problem 2359. Ostrov BE, Goldsmith DP, Athreya BH. Differentiationof systemic juvenile rheumatoid arthritis from acutelymphoblastic leukemia near the onset of disease. JPediatr 1993; 122: 595-8.10. Musiej-Nowakowska, Rostroposicz-Denisiewicz K.Differential diagnosis of neoplastic and rheumatic dis-eases in children. Scand J Rheumatol 1986; 15: 124-8.11. Costello PB, Brecher ML, Starr JI, Freeman Al, GreenFA. A prospective analysis of the frequency, course,and possible prognostic significance of the joint mani-festations of childhood leukemia. J Rheumatol 1983;10: 753-7.12. Silverstein MN, Kelly PJ. Leukemia with osteoarticularsymptoms and signs. Ann Intern Med 1963; 59: 637-45.13. Schaller J. Arthritis as a presenting manifestation ofmalignancy in children. J Pediatr 1972; 81: 793-7.14. Revesz T, Kardos G, Kajtar P, Schuller D. The adverseeffect of prolonged prednisolone pretreatment in chil-dren with acute lymphoblastic leukemia. Cancer 1985;55: 1637-40.

Childhood acute lymphoblastic leukaemia masquerading as primary skeletal problem

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Childhood acute lymphoblastic leukaemia masquerading as primary skeletal problem

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