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Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 365-367
CORRESPONDENCE
Differentiating Juvenile Myelomonocytic Leukemia From Infectious
Disease
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LETTER |
To The Editor:
Two recent articles in BLOOD1,2 review the
findings and outcome of juvenile myelomonocytic leukemia (JMML). Both
omit an important aspect of JMLL: its differentiation from infectious
disease. Several disseminated microbial infections of infancy can
result in persistent fever, failure to thrive, hepatosplenomegaly, skin
lesions, anemia, thrombocytopenia, and myelomonocytosis, including
Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus-6
(HHV-6), histoplasma, mycobacteria, and toxoplasma. Thorough
investigation for infection is needed in infants with these findings to
avoid erroneous diagnosis and mistaken interventions.
Herrod et al3 reported two infants with persistent EBV
infection and findings consistent with JMML, including increased
numbers of F and i cells and abnormal granulocyte-macrophage colony
formation in vitro. Both recovered without treatment and remained well.
This raises the possibility that some of the long-term survivors
reported by Niemeyer et al and Arico et al had similar infections
rather than leukemia. Neonatal CMV and HHV-6 infections can also mimic
JMML.4,5 Might erroneous diagnosis account for the better
prognosis reported for patients with JMML who are less than 6 months
old?2
The excellent reviews of Niemeyer et al and Arico et al suggest that
JMML represents a group of diseases rather than a single entity.
Careful investigation for microbial associations, including more
recently identified herpesviruses, might contribute to
understanding pathogenesis as well as to diagnosis and
management.
Donald Pinkel
Driscoll Children's
Hospital
Corpus Christi, TX
| |
REFERENCES |
1. Niemeyer CM, Arico M, Basso G, Biondi A, Cantú Rajnoldi A,
Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G, Locatelli F, Mann
G, Stollmann-Gibbels B, Van't Veer-Korthof, van Wering E, Zimmerman M,
and members of the European Working Group on Myelodysplastic Syndromes
in Childhood: Chronic myelomonocytic leukemia in childhood: A
retrospective analysis of 110 cases. Blood 89:3534, 1997
2.
Arico M,
Biondi A,
Pui C:
Juvenile myelomonocytic leukemia.
Blood
90:479,
1997[Free Full Text]
3.
Herrod H,
Dow L,
Sullivan J:
Persistent Epstein-Barr virus infection mimicking juvenile chronic myelogenous leukemia: Immunologic and hematologic studies.
Blood
61:1098,
1983[Abstract/Free Full Text]
4.
Kirby M,
Weitzman S,
Freedman M:
Juvenile chronic myelogenous leukemia: Differentiation from infantile cytomegalovirus infection.
Am J Pediatr Hematol Oncol
12:292,
1990[Medline]
[Order article via Infotrieve]
5.
Lorenzana A,
Lyons H,
Sawaf H,
Higgins M,
Carrigan D,
Emmanuel P:
Human herpes virus-6 (HHV-6) infection in an infant mimicking juvenile chronic myelogenous leukemia (JCML).
J Pediatr Hematol Oncol
19:370,
1997
We are grateful to Dr Pinkel for his carefully considered remarks. We
fully agree that some infectious disease can mimic JMML, thus
jeopardizing the interpretation of some cases. In particular, Dr Pinkel
raises the question of whether some of the long-term survivors we
described, in fact, have JMML. Although such suspicion is obviously
warranted, our experience indicates that the vast majority of cases
that fit the diagnostic picture of JMML represent leukemia and not an
infectious process. Even when the patients show rapid recovery with or
without "minimal treatment," reactivation of the disease may
occur. In some cases these recurrences have an accelerated phase,
mirroring that in patients with rapidly fatal JMML. We cannot rule out
infectious diseases as the origin of some of the more unusual cases of
JMML that have been reported in the medical literature, but we
do not believe these exceptions account for more than 10% of the
total number. Perhaps current advances in the diagnosis will help to
resolve this intriguing issue.
Maurizio Aricò
IRCCS Policlinico S. Matteo
Pavia,
Italy
Andrea Biondi
Ospedale S. Gerardo
Monza,
Italy
Ching-Hon Pui
St Jude Children's Research
Hospital
Memphis, TN
We have recently published the results of a retrospective analysis of
110 children with chronic myelomonocytic leukemia (CMML).1
There has since been an international consensus to rename the disease
juvenile myelomonocytic leukemia (JMML). The new term JMML will include
all leukemias of childhood previously classed CMML,1,2
juvenile chronic myelogenous leukemia (jCML),3,4 or
infantile monosomy 7 syndrome,3 because their clinical and
biological similarities suggest that they are spectrums of the same
disease. We believe that the broad agreement on nomenclature will
facilitate cooperative treatment trials and hasten research on the
pathogenesis of JMML.
As addressed by Dr Pinkel, the clinical and morphological picture of
JMML can be mimicked by a variety of infectious organisms. In addition,
granulocyte-macrophage colony-stimulating factor hypersensitivity of
myeloid progenitor cells, thought to play a central role in the
pathogenesis of JMML,5 has been noted in vitro in children
with viral infections.6 A basic tenet for the definition of
myeloid leukemias is the demonstration of the clonal origin from a
malignant hematopoietic progenitor cell.7 The clonal nature
is often inferred by evidence of a chromosomal abnormality or an
activating mutation of a proto-oncogene. In this respect about half of
the children with JMML have evidence of a clonal disorder; 35% are
known to have a chromosomal abnormality1 and 15% to have a
point mutation of the Nras or Kras oncogene in their
hematopoietic cells.8 More recently, the study of
X-chromosome inactivation patterns showed evidence for monoclonal
origin of mononuclear cells in all female JMML patients
analyzed.9 In the absence of a marker of clonality, the
establishment of the diagnosis JMML and firm exclusion of an infectious
origin can be difficult.
To address this issue in our retrospective study1 we
collected data on the serology for cytomegalovirus (CMV; n = 56),
herpes virus type I (HSV; n = 27), and Epstein-Barr virus (EBV;
n = 51) from the time of diagnosis. Thirty-eight percent of children
were positive for CMV, 44% for HSV, and 47% for EBV. The prevalences
of antibodies to these viruses were similar to those observed in normal
infant populations in Western Europe.10-13 There were no
significant differences in age at diagnosis or length of survival
between JMML patients with or without previous or recent CMV, HSV, or
EBV infection. Dr Pinkel raises the concern that some of our long-term
survivors might have had infections rather than leukemia. Of the seven
patients with a survival of more than 5 years without bone marrow
transplantation, four have succumbed to their disease (Table 7 in
Niemeyer et al1). Of the three remaining patients, one girl
currently alive with disease 6.5 years after diagnosis is known to have
an Nras mutation (A. Biondi, personal communication). Another
patient had monosomy 7 in his bone marrow cells documented
twice within 6 months after diagnosis, whereas a normal karyotype was
found 4 and 9 years later. He had no evidence of disease when seen last
9.6 years after diagnosis.14 The patient with the longest
survival, currently 13 years after diagnosis, had no marker of
clonality. His smears and clinical data were thoroughly reviewed, but
it cannot be excluded that he suffered from an infection rather
than from leukemia. Viral studies from the time of the diagnosis were
not available.
We agree with Dr Pinkel that a careful investigation for an infectious
cause is mandatory in all children suspected as suffering from JMML.
Until the chromosomal and molecular abnormalities of the majority of
JMML patients with so-called "normal karyotype" have been
unraveled, the diagnosis of JMML will have to be based on a
number of clinical and laboratory features (Table 1).
The suggestive clinical features, the minimal laboratory criteria, and
the criteria requested for definite diagnosis may prove to be a
guideline in establishing the diagnosis of JMML.
For the European Working Group of MDS in Childhood
(EWOG-MDS):
C.M. Niemeyer
Universitäts-Kinderklinik
Freiburg, Germany
S. Fenu
Cattedra di Ematologia
Universitá degli Studi di
Roma
Roma, Italy
H. Hasle
Aarhus
Kommunehospital
Aarhus, Denmark
G. Mann
St Anna
Kinderspital
Vienna, Austria
J. Stary
2nd Medical
Faculty, Charles University
2nd Clinic of Pediatrics
Pragues, Czech
Republic
E. van Wering
Dutch Childhood Leukemia Study
Group
The Hague, The Netherlands
| |
REFERENCES |
1. Niemeyer CM, Aricó M, Basso G, Biondi A, Cantú
Rajnoldi A, Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G,
Locatelli F, Mann G, Stollmann-Gibbels B, van't Veer-Korthof, van
Wering E, Zimmermann M, and members of the European Working Group on
Myelodysplastic Syndromes in Childhood: Chronic myelomonocytic leukemia
in childhood: A retrospective analysis of 110 cases. Blood 89:3534,
1997
2.
Castro-Malaspina H,
Schaison G,
Passe S,
Pasquier M,
Berger R,
Bayle-Weisgerber C,
Miller D,
Seligmann M,
Bernard J:
Subacute and chronic myelomonocytic leukemia in children (juvenile CML).
Cancer
54:675,
1984[Medline]
[Order article via Infotrieve]
3.
Freeman MH,
Estrov Z,
Chan HSL:
Juvenile chronic myelogenous leukemia.
Am J Pediatr Hematol Oncol
10:261,
1988[Medline]
[Order article via Infotrieve]
4.
Passmore SJ,
Hann IM,
Stiller CA,
Ramani P,
Swansbury GJ,
Gibbons B,
Reeves BR,
Chessels JM:
Pediatric myelodysplasia: A study of 68 children and a new prognostic scoring system.
Blood
85:1742,
1995[Abstract/Free Full Text]
5.
Emanuel PD,
Bates LJ,
Castleberry RP,
Gualtieri RJ,
Zuckerman KS:
Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors.
Blood
77:925,
1991[Abstract/Free Full Text]
6.
Lorenzana A,
Lyons H,
Sawaf H,
Higgins M,
Carrigan D,
Emmanuel P:
Human herpes virus-6 (HHV-6) infection in an infant mimicking juvenile chronic myelogenous leukemia (JCML).
J Pediatr Hematol Oncol
19:370,
1997
7.
Fialkow PJ,
Gartler SM,
Yoshida A:
Clonal origin of chronic myelocytic leukemia in man.
Proc Natl Acad Sci USA
58:1468,
1967[Free Full Text]
8.
Kalra R,
Paderanga DC,
Olson K,
Shannon KM:
Genetic analysis is consistent with the hypothesis that NF 1 limits myeloid cell growth through p21ras.
Blood
84:3435,
1994[Abstract/Free Full Text]
9.
Busque L,
Gilliland DG,
Prchal JT,
Sieff CA,
Weinstein HJ,
Sokol JM,
Belickova M,
Wayne AS,
Zuckerman KS,
Sokol L,
Castleberry RP,
Emanuel PD:
Clonality in juvenile chronic myelogeous leukemia.
Blood
85:21,
1995[Abstract/Free Full Text]
10.
Leinikki P,
Granström M-L,
Santavuori P,
Pettay O:
Epidemiology of cytomegalovirus infections during pregnancy and infancy.
Scand J Infect Dis
10:165,
1987
11.
Ahlfors K,
Ivarsson S-A,
Johnsson T,
Svensson I:
Congenital and acquired cytomegalovirus infections.
Acta Paediatr Scand
67:321,
1978[Medline]
[Order article via Infotrieve]
12.
Stuart-Harris C:
The epidemiology and clinical presentation of herpes virus infections.
J Antimicrob Chemother
12:1,
1983[Free Full Text]
13.
Lamy ME,
Favart AM,
Cornue C,
Mendez M,
Segas M,
Bortonboy G:
Study of Epstein-Barr virus (EBV) antibodies.
Acta Clin Belg
37:281,
1982[Medline]
[Order article via Infotrieve]
14.
Stollmann B,
Fonatsch C,
Havers W:
Persistent Ebstein-Barr virus infection associated with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders.
Br J Haematol
60:183,
1985[Medline]
[Order article via Infotrieve]
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