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Vertebral Compression Fracture as a Presenting Feature ofAcute Lymphoblastic Leukemia in Children

RAUL C. RIBEIRO, MD, CHING-HON PUI,MD.*t AND MICHAEL J. SCHELL, PHDS

Twenty-four (1.6% ) of 1466 children with acute lymph oblastic leukemia (ALL ) treated a t S t. JudeChildrens R esearch H ospital had vertebral compression fractures at d iagnosis. Wh en compared withpatients without this complication, they were more likely to have good prognostic features, including aleukocyte count of greater than 25 X 109/1, a leukemic cell DNA index of greater than 1.15, andhyperdiploidy (>50 chromosom es). Complete remissionof ALL was induced in all patients, and symp-toms of vertebral compression fractures abated following antileukemia therapy. Although the diagnosisof ALL was delayed for some patients because this unusual presen ting complication was not recognizedas such , their treatment outcome was as good as that for other children with standard-risk ALL.Cumer61589-592,1988.

ERTEBRALCOMPRESSZONRACTURE is a rare com-plication of childhood acute lymphoblastic leuke-mia (ALL).- Because the presenting symptoms inchildhood ALL patients with this complication are gen-erally atypical, the diag nosis of leukemia can be delayed,resulting in increased complications. Based on case re-ports, Blatt et al. have suggested that thes e cases repre-sent a unique subset of ALL characterized by low leuke-mic cell burden. Otherwise, little is known about thepresenting features or outcome of these patients. Wereport the clinical and biologic features of 24 consecu-tive children with vertebral comp ression fractures asso-ciated with ALL. We found that these children usuallyhave favorable presenting features for leukemia and thatthey have a relatively good treatme nt outcome, com pa-rable to that of others with standard-risk leukemia.

From the Departments of *Hematology/Oncology, and SBiostatis-tics and Information Systems, St. Jude Childrens Research Hospital,Memphis, and the ?Division of Hematology and Oncology, Depart-ment of Pediatrics, University of Tennessee at Memphis, College ofMedicine, Memphis, Tennessee.Supported in part by Grants CA-20180 and CA-21765 from theNational Cancer Institute, and by the American Lebanese Syrian As-sociated Chanties.The authors thank Dr. . Thomas Look for DNA content detenni-nations, Drs. Sue Melvin and Frederick Behm for immunologic stud-ies, Drs. Dorothy L. Williams and Susana C. Raimondi forcytogeneticanalyses, Ms. Marlene Jacks for typing and Ms. Linda Daniels formanuscript editing.Address for reprints: Ching-Hon h i , MD, t. Jude Childrens Re-search Hospital, 332 North Lauderdale, P.O. Box 318, Memphis, T N38101.Accepted for publication August 25, 1987.

Patients and MethodsFrom 1970to 1986, 1466 consecutive, previously un-treated children with ALL were admitted to St. JudeChildrens Research H ospital. Routine chest roentgeno-grams were performed for all patients. Children withvertebral compressio n fractures were identified by bo thcomp uter-assisted review of case material from the med-ical records and radiology departments and by chartreview of each case. Patients were enrolled in one of fivesuccessive clinical trials afier informed consent was ob-tained. Details of the treatment plans have been de-scribed previously.*-*

Leukemic Cell Phenotype StudiesThe diagnosis of ALL was based on morphologic andcytochemical staining properties and, more recently,cases were classified according to French-American-British (FAB) criteria. 3 Leukemic cell immunopheno-type was determined from reactivity with monoclonalantibodies to lymphoid-associated antigens, including

J5 (common ALL antigen, CD-lo), TI 1 (CD-2), TI01(CD-5) and T3 (CD-3).I4 Blast cells were also tested forsurface and cytoplasmic immunoglobulin and rosetteformation with sheep erythrocytes.DNA Content Determination

Leukemic bone marrow samples were stained withthe DNA-specific dye, propidium iodide, and analyzedby flow cytometry, as previously described. The DN Aindex (ratio of DNA co ntent in leukemicGO/G1 cells to

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590 CANCER ebruary I 1988 No. 3TABLE. Presenting Clinical and Laboratory Characteristics of Patients With Vertebral Compression Fracture

Leukocyte Hem oglobin Platelet Leukem ic cellPatient Age cou nt level countno. (yr) Race Sex (X 109/1) (ddU (X I09/1) lmmunophenotype D NA index PloidyI 5.3.. 4. 43 4. I4 16.25 5 .6 18.37 2.48 6.19 9.510 6.4

11 7.5I ? 9.813 9. 314 5.615 2. 116 3.917 2.818 7.419 4.220 4.021 4.22 6.723 12.924 10.1

3W FW MW MW MW FW MW MW FW FW FW FW MW FW FW MW FW FW FW FW FW FW MW MW F

24.06.96.4I .810.54. 06.6.74.53.42.34.29.116.06 .9.885.022.57.85.45.8.2.44 .1

7.95.37. 110.02.97. 36. 68.57.89. 67. 610.39. 25. 911.55.86.55. 22.45.48.510.77.911.4

22NA9I96181501310626053206280483040 0819825746106562I7372

NANANANANANANANACommonCALLA-NACommonCommonCommonCALLA-CommonCommonCommonNACommonNAPre-B*CommonCommon

NANANANANANANANANANANA1.171.171 .ooNA1.181.211.171.231.18NAI .oo1.151.12

NANANANANANANANAPseudodiploidDiploidDiploidHyperdiploidHyperdiploidHypodiploidHyperdiploidHyperdiploidHyperdiploidHyperdiploidNAHyperdiploidNAPseudodiploidHyperdiploidHvrxrdiuloid

NA: not available; CALLA: negative for com mo n acute lyrnphoblas-tic leukemia antigen.

that of normal diploid GO/Gl cells) was determined.This measure correlates closely with chromosome num-b e r (ploidy); hence, leukemic cells with a normal chro-mosome number have a DNA index of 1 .O.Cytogenetic Studies

Bone marrow samples were prepared for cytogeneticanalysis by a direct technique developed for ALL and amodified trypsin-Giemsa technique for chromosomebanding.I6 Cases were classified according to the Inter-national System of Human Cytogenetic Nomenclature(1985)''

Statistical AnalysisFisher's exact test for contingency tables was used to

compare differences in the distribution of presentingclinical features and the remission induction rates forpatients with or without vertebral compression fracture.Bonferoni correction was used to adjust for multiplecomparisons." Since 1 1 features were compared, any Pvalue less than 0.05/11 (0.0045) was considered to bestatistically significant. Time-to-failure curves wereconstructed by the Kaplan-Meier procedure, and dif-ferences were analyzed by the Cox-Mantel test. Time tofailure was defined as the interval between remission

Presence of cytoplasmic immunoglobulin.

induction and relapse or death due to any cause. Pa-tients who did not enter complete remission were as-signed a failure time of zero.

ResultsOf 1466 children with ALL, 24 (1.6%) presented with

vertebral compression fractures. The initial clinical andlaboratory characteristicsof these patients are shown inTable 1. At diagnosis, the 15 girls' and nine boys' agesranged from 2.4 to 18.3 years (median, 5.8 years), leu-kocyte counts from 1.8 to 85 X l o9 / ] (median, 6.2X 109/1),hemoglobin levels from 2.4 to 11.5 g/dl (me-dian, 7.7 g/dl) and platelet counts from 8 to 562 X 109/1(median, 72 X 109/l).No patient had a mediastinal massor central nervous system leukemia at diagnosis. Theliver or spleen was palpable more than 5 cm below thecostal margin in eight patients. Cell morphology was L1in 13 patients and L2 in two patients tested. Of the 13cases tested for leukemic cell immunophenotype, tenhad common and one pre-B ALL; the remaining twocases did not express any lineage-specific markers orcommon ALL antigen. Notably, there were no cases ofT-cell ALL. Of the 1 1 cases tested, seven had a blast cellDNA index of greater than 1 .1 5 . Karyotype analysis ofleukemic cells from 14 patients disclosed that nine caseswere hyperdiploid with more than 50 chromosomes,


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Vol. 61 VERTEBRALOMPRESSIONRACTUREN ALL * Ribeiro ct a/ . 59 1two pseudodiploid (46 chromosomes with structural ab-normalities), two diploid, and one hypodiploid (lessthan 46 chromosomes).Comparisons of the presenting clinical and biologicfeatures disclosed that patients w ith vertebral compres -sion fracture were significantly more likely to have leu -kocyte cou nts < 25 X 109/1and to have leukemic cellDNA index >1.15 than were those without this com pli-cation (Table 2). They also tended to have leukem ic cellhyperdiploidy. There were n o significant differences be-tween the tw o groups in sex, age, race, liver and spleensize, hemoglobin level, platelet count, and FAB mor-phology.The duration of initial symptoms ranged from 1 to 22weeks (median, 7 weeks). Nineteen patients had backand leg pain as their initial chief comp laint. F ive of thepatients were unable to walk because of intense pain.Despite seeking medical attention, the diagnosis of leu-kemia was delayed (5 to 13 weeks) for six patients be-cause initial findings from physical examination, radio-graphic examination of the spine (three patients), andcomplete blood counts (two patients) were normal.Twe nty-two patients had multiple vertebral compres-sion fractures and two had only one vertebra involved.In addition to vertebral compression fractures, 1 1 pa-tients had extensive spinal osteoporosis. Midthoracicand upper lumbar vertebrae were most frequently in-volved (17 and 14 cases, respectively). Seven patientshad involvement of both thoracic an d lum bar vertebrae.In no instan ce were cervical vertebrae affected.Two of the six patients tested had elevated serum cal-cium levels at diagnosis (1 l .7 and 12.7 mg/dl); serumparathormone level was elevated ( 1350 ng/l; normal< 88 5 ng/l) in one of the two. The hypercalcemia wascorrected after antileukemic therapy but the serum cal-cium level was again elevated in on e patient a t relapse ofleukemia.

All patients completely recovered from vertebralcompression fractures. Twen ty-one patients were free ofpain an d ambulatory within 4 weeks from the beginningof antileukemic therapy. Only three patients required anorthopedic brace and physical therapy for 2 to 3 months.Complete remission was induced in all 24 patientsand 16 remained free of leukemia for 2 mo nths to 15.2years (median, 4.3 years). When the 23 patients withvertebral comp ression fracture and presenting leukocytecoun ts of less than 25 X 109/1were compared to the 943patients who also had leukocyte counts of less than 25X 109/1 but had no such com plication, there was nodifference in the treatment outcom e. A mong those pa-tients, 53% with vertebral compression fractures com-pared with 5 1% without the complication were esti-mated to be in complete remission 4 years after diag-nosis.

TABLE. Comparisons of Clinical and Biologic Features BetweenChildren With or Without Vertebral CompressionFracture at Diagn osis of AL LVertebralcompressionfracture

FeatureLeukocytesDN Aindex*KarYOtYpeploidy*SexAge (Yr)

(x 109/1)Category ] . I 55 1 . 1 5HyperdiploidytOthersGirlsBoys 2-10I0

Present2317495159204

Absent PValue943 0.001499107 0.002436157 0.00640462 1 0.0682 I956 0.08486

A L L acute lymphoblastic leukemia.* Data no t available for some patients.t >50 chromosomes.

DiscussionChildren with vertebral compression fractures atdiagnosis of ALL were demonstrated to be more likelyto have leu kocyte counts of less than 25 X 109/1, leuke-mic cell DNA indexes of greater tha n 1.15 and hyper-diploidy-favorable presenting features known to be as-sociated with standard-risk Although verte-bral compression fractures are associated with thoseclassic indicators of go od p rognosis, results of our anal-ysis disclosed that the presence of this com plication has

no independent prognostic value.Bone pain and radiographically detected skeletalchanges are comm on in children with ALL. The radio-graphic abnormalities include radiolucent metaphysealbands, periosteal reaction, osteolysis, and osteoscler-The vertebral column is involved less oftenthan are the long bones. Spinal os?eoporosis eading tovertebral compression fractures has been reportedrarely.- Baty and V0gt3 reported vertebral involvementin two of 43 children with leukemia. Blatt ef a/. de-scribed this complication in two of 350 patients withALL. Leheup et al. noticed this complication in one of250 patients. Non e of the 137 patients in a series studiedby Rajantie et al. had vertebral com pression fractures.20Our study confirms the rarity of this axial skeletal lesion,occu mn g in fewer than 2% of our newly diagnosed pa-tients with childhood ALL.The mechanisms that cause osteoporosis in childrenwith ALL are uncertain. Release of parathormone or anosteoclast activating factor by leukem ic cells has beenimplicated in the demineralization p r o ~ e s s . * ~ * ~ ~n thisstudy, serum calcium was increased in two of six pa-tients tested at diagnosis, an d serum paratho rmone was


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