Medical and Pediatric Oncology 35:421–425 (2000)
Concurrent Langerhans Cell Histiocytosis and Myelodysplasia in Children
Giammarco Surico, MD,1* Paola Muggeo, MD,1 Nicola Rigillo, MD,1 and
Helmut Gadner, MD2
Background. Langerhans cell histiocytosis
(LCH) is characterized by the proliferation of
abnormal histiocytes (Langerhans cells), whose
origin as a reactive process or a neoplastic dis-
order is still poorly understood. Although LCH
has been recorded as being associated with ma-
lignant neoplasms, concurrence of LCH and
myelodysplastic syndrome has not been re-
ported so far. Procedure. We report on four
children aged 23, 25, 26, and 53 months with
multisystem LCH with organ dysfunction (bone
marrow and liver) whose bone marrow pic-
tures, taken at diagnosis, revealed the presence
Key words: Langerhans cell histiocytosis; myelodysplasia; bone marrow; pediatric
oncology
INTRODUCTION
Langerhans cell histiocytosis (LCH) is characterized
by the proliferation of abnormal histiocytes with distinc-
tive morphologic and immunohistochemical features
(such as S-100 protein and CD1a antigen), known as
Langerhans cells. Although a recently demonstrated
monoclonality suggests a neoplastic origin of these cells
[1,2], the pathogenesis of LCH—whether it originates as
a reactive process or a neoplastic disorder—is still poorly
understood [3].
The clinical heterogeneity of the disease ranges from
solitary lytic bone lesions with a favorable course to a
disseminated disorder, occurring in young children, with
fatal evolution mainly from progressive organ failure
(bone marrow, liver, lungs). There have been previous
reports of patients with LCH and associated malignant
neoplasms, in which LCH occurred prior to, concurrent
with, or after malignant lymphoma, leukemia, or other
solid tumors [4–8]. Myelofibrosis has recently been
found at the onset of LCH [9], but, so far, the simulta-
neous occurrence of LCH and the myelodysplastic syn-
drome has not been reported.
We report on four children with multisystem LCH and
organ dysfunction treated at our institution. The retro-
spective review of bone marrow slides, taken at diagno-
sis, revealed the presence of myelodysplastic abnormali-
ties (according to the modified FAB criteria) [10–14] in
all four patients.
PATIENTS
Fourteen patients were diagnosed with LCH according
to the Histiocyte Society criteria [15], from May, 1992,
© 2000 Wiley-Liss, Inc.
of myelodysplastic abnormalities (RA, RAEB,
RAEB-t). Results. We suggest that the com-
monly used expression of “organ dysfunction,”
which refers to clinical and functional alter-
ations, could be explained by a myelodysplas-
tic-like disorder. Conclusions. The contempo-
rary presence of both events may provide a
better understanding of the pathogenesis of
LCH, especially in young children with multi-
system disease and organ dysfunction, who are
known to have a very poor outcome. Med. Pe-
diatr. Oncol. 35:421–425, 2000.
© 2000 Wiley-Liss, Inc.
to September, 1996, at the Pediatric Hematology-
Oncology Department II, Pediatric Clinic, University of
Bari. They were treated according to the international
studies LCH-I [16] and LCH-II (Fig. 1). All 14 patients
had a bone marrow aspirate examined at diagnosis in
order to complete the staging of the disease.
There were five males and nine females, with a me-
dian age at diagnosis of 34 months (range 18–100
months). Three of fourteen (45, 41, and 30 months old)
presented with unisystemic LCH involving the skin, ear,
and eye. Eleven of fourteen children, with a median age
at diagnosis of 34 months (range 18–100 months), pre-
sented with multisystem disease, four with organ dys-
function and seven without. The four patients with organ
dysfunction were younger and had disseminated LCH
associated with bone marrow and liver pathology (Table
I). Their disease had an aggressive course and was resis-
tant to treatment, leading to progressive bone marrow
failure and eventual death.
The last patient observed at our institution (patient 4)
presented a more compromised bone marrow picture,
which suggested a myelodysplastic disorder. We there-
fore reviewed the bone marrow slides taken during di-
1
Department of Pediatric Hematology and Oncology, II Pediatric
Clinic, University of Bari, Bari, Italy
2
St. Anna Children’s Hospital, Vienna, Austria
*Correspondence to: Giammarco Surico, MD, Sezione di Onco-
Ematologia Pediatrica, II Clinica Pediatrica, Policlinico, Piazza Giulio
Cesare, 70124 Bari, Italy. E-mail: n.rigillo@pediatria2.uniba.it
Received 9 November 1999; Accepted 11 March 2000
422 Surico et al.
Fig. 1. LCH II protocol. Patients with multisystem disease (whether
or not organ dysfunction is diagnosed) are elegible for treatment.
Low-risk patients are patients with multisystem disease, >2 years of
age, without involvement of the hematopoietic system, liver, lungs, or
spleen. Standard-risk patients are patients with multisystem disease,
<2 years of age, or >2 years old with involvement of hematopoietic
system, liver, lungs, or spleen. PDN, prednisone; VBL, vinblastine;
VP16, etoposide; 6-MP, mercaptopurine.
agnosis in the other three patients with organ dysfunc-
tion. Myelodysplastic abnormalities were also detected in
them, but not in the ten patients with LCH without organ
dysfunction.
To test the clonality of the myelodysplastic disorder,
and also considering the previous reports about LCH and
its clonality [1,2], we tried to perform an FISH analysis
on bone marrow samples. We were looking for mono-
somy of chromosome 7 and trisomy of chromosome 8,
the most recurrent cytogenetic change found in child-
hood myelodysplastic syndromes [10,14]. Unfortunately,
FISH analysis was evaluable only in patients 2 and 4, in
whom no such alterations were found. Details regarding
the four propositi follow (see also Table I).
Case 1
A 23-month-old boy presented with multisystem LCH
with organ dysfunction (anemia and hypoalbuminemia).
A lymph node biopsy together with a bone marrow tre-
phine biopsy revealed the presence of Langerhans cells,
and immunohystochemistry was positive for S-100 and
CD1a. On light microscopy, the bone marrow aspirate
revealed a hypoplastic bone marrow, with 2% blast cells.
The child was treated with chemotherapy, but the disease
progressed (enlargement of the liver and spleen, severe
anemia, thrombocytopenia, and hypoalbuminemia), and
he died 9 months after diagnosis. A retrospective review
of the bone marrow slides taken at diagnosis confirmed
hypoplasia of the bone marrow, with 7% blasts, findings
that are compatible with a myelodysplastic disorder with
lymphoblastic proliferation (Fig. 2).
Case 2
A 25-month-old boy presented with osteolytic foci in
the mandible, skin and lung lesions, lymph node swell-
ing, and otitis. Bone and skin biopsies were performed,
and the histology (based on morphology) revealed the
presence of Langerhans cells. The bone marrow was free
of LCH on biopsy, but he had anemia and thrombocyto-
sis. Chemotherapy was unsuccessful, and he died 22
months after diagnosis. In this case too, despite the ap-
parent absence of involvement by LCH, a retrospective
review of bone marrow slides revealed the presence of
myelodysplastic abnormalities (with 3% myeloblasts;
Fig. 3), corresponding to the clinical manifestations of
bone marrow impairment.
Case 3
The patient, a 28-month-old girl, presented with a
typical eosinophilic granuloma in the left femur (S-100
protein was positive; CD1a was not done). Laboratory
findings showed anemia, thrombocytopenia, and hypoal-
buminemia. Further examinations revealed the involve-
ment of multiple sites. Some histiocytes and hyperplasia
of the red cell line were detected in the bone marrow on
light microscopy. The immunology revealed a low posi-
tivity for CD1a. Chemotherapy was unsuccessful, and
she died 6 months after diagnosis despite salvage therapy
that included cyclosporin A. The retrospective review of
bone marrow slides (light microscopy) revealed dyser-
ythropoiesis, defective myelogranules, and 5% blasts.
These findings are compatible with the myelodysplastic
syndrome (refractory anemia; Fig. 4).
Case 4
A girl aged 4 years, 5 months presented with an os-
teolytic lesion in the left femur and skin lesions. Bone
and skin biopsies were indicative of LCH (S-100 protein
and CD1a were positive). Mild anemia and thrombocy-
topenia were also detected. The bone marrow aspirate
showed some atypical granules in the myeloid cells and
8% myeloblasts. However, considering the skin and bone
biopsy results, LCH was diagnosed, and she received
chemotherapy. A bone trephine, bone marrow biopsy,
and liver biopsy suggested liver and bone marrow in-
volvement by LCH (S-100 protein-positive). Another
bone marrow biopsy showed the presence of 15% my-
eloblasts, with red cell line hyperplasia, histiocytes with
red cell phagocytosis and plasma cells. A diagnosis of
myelodysplastic syndrome (RAEB-t) was suspected and
confirmed by a retrospective analysis of the bone marrow
slides (Fig. 5), bone marrow trephine, and liver biopsy
previously done. The child was treated with high-dose
chemotherapy followed by bone marrow transplantation,
but unfortunately myeloblasts in the bone marrow re-
curred, and she died 20 months after diagnosis.
DISCUSSION
The association between LCH and various malignant
diseases as previously reported [4–8] is marked by dif-
ferent patterns of evolution. The cancers have been found

TABLE I. Clinical Characteristics of Patients With Multisystem LCH and Organ Dysfunction
(Liver and Bone Marrow)
Age at
diagnosis
Patients (months) Sex Sites
1 23.1 M Bone, ear, skin,
lymph nodes,
mediastinum
2 25.2 M Bone, ear, skin,
lymph nodes, lungs
3 26 F Bone, skin, spleen,
liver, bone marrow
4 53 F Bone, skin, liver,
bone marrow
Fig. 2. Patient 1. Bone marrow aspirate (sample taken at diagnosis),
showing bone marrow hypoplasia, defects of granules in the myeloid
cells, and presence of blasts.
before, concurrent with or after the diagnosis of LCH.
Our patients presented a myeloproliferative disorder at
the time of the LCH diagnosis and prior to chemo-
therapy. Interestingly, the children reported here repre-
sent the totality of patients affected by LCH with organ
dysfunction treated at our institution according to proto-
cols LCH-I and LCH-II. They all showed a younger age
at diagnosis and multisystem disease, with severe organ
dysfunction (bone marrow and liver). All four had a poor
outcome, mainly because of bone marrow failure, despite
polychemotherapy and salvage treatment with cyclospor-
in A. The clinical pictures of organ dysfunction in our
patients and the bone marrow findings correspond to
those of a myelodysplastic disorder according to the FAB
classification. In fact, the retrospective review of the
bone marrow slides taken at the onset of the disease
revealed the presence of myelodysplastic features, with
different percentages of blasts. We could also detect he-
mophagocytosis in the last bone marrow aspirate of pa-
tient 4, probably secondary to infection [17]. These ob-
LCH and Myelodysplasia 423
Therapy Status
LCH-I arm A + arm B + Dead
cyclosporin A
LCH-I arm B + arm A + Dead
cyclosporin A
LCH-I arm A + Dead
polychemotherapy + LCH-I
arm B + cyclosporin A +
LCH-S
LCH-II arm B + Arm A + Dead
idarubicin-cytarabine + bone
marrow transplantation
Fig. 3. Patient 2. Bone marrow aspirate (sample taken at diagnosis),
showing dyserythropoiesis (nuclear atypia), dysmyelopoiesis (defects
of granulation), presence of blasts, and a micromegakaryoblast.
servations appear more relevant insofar as no such
myelodysplastic abnormalities were detected in the bone
marrow aspirates of the ten patients with multisystem
LCH who did not exhibit organ dysfunction. In the same
period of time only one other patient in our clinic pre-
sented with myelodysplasia. He was found to have Pear-
son’s syndrome.
It is difficult to give an explanation for the simulta-
neous presence of both events. We could only hypoth-
esize that the abundant expression of cytokine in LCH
[18], especially in disseminated LCH [19], may play a
role in the proliferation and activation of both bone mar-
row progenitors and peripheral Langerhans cells. Dys-
regulation in cell maturation and differentiation may be
responsible for the myeloproliferative disorder and the
typical LCH lesions observed. The simultaneous pres-
ence of both events may thus provide a clue to the patho-
genesis of LCH, especially in young children with mul-
tisystem disease and organ dysfunction. In particular, we
would suggest that the commonly used expression “or-
424 Surico et al.

Fig. 4. Patient 3. Bone marrow aspirate. Samples taken at diagnosis

(A) and during treatment (B), showing dyserythropoiesis (nuclear
lobulation, binucleated erythroblasts; A,B), histiocytes (B), and pres-
ence of blasts (A).

gan dysfunction,” which refers to a clinical and func-

tional alteration, could be explained by a myelodysplas-
tic-like disorder involving also the liver (as occured in
patient 4). This may be particularly relevant to children
with hemopoietic organ dysfunction who die mainly
from organ failure [20–23].
The bone marrow of children with LCH and hemato-
poietic organ dysfunction should be carefully evaluated
at diagnosis, looking for myelodysplastic abnormalities,
and carefully followed in order to detect as early as pos- Fig. 5. Patient 4. Bone marrow aspirate. Samples taken at diagnosis
sible the progression to overt acute leukemia. Our pre- (A), during treatment (B), and 2 months later (C), showing dysmy-
elopoiesis (defect of granules, bizzare nuclear shape; A,B) dyseryth-
liminary observations, although limited to only four pa- ropoiesis (nuclear atypia; A,B), presence of several blasts (A–C), and
tients, should be expanded by prospective studies hemophagocytosis (C).
focusing on different stages of cell maturation and dif-
ferentation in the bone marrow and in the peripheral
Dr. Teresa Santostasi, and Dr. Giuseppe Loiacono for
blood. Understanding of the pathogenesis of this inter-
their cooperation.
esting and intriguing disease may thereby be improved.

REFERENCES
ACKNOWLEDGMENTS
1. Willman CL, Busque L, Griffith BB, et al. Langerhans’ cell his-
We are grateful to Prof. Oskar Haas for the FISH tiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl
analysis. We also thank Prof. Angelo Cantù-Rajnoldi, J Med 1994;331:154–160.

2. Yu RC, Chu C, Buluwela L, Chu AC. Clonal proliferation of
Langerhans cells in Langerhans cell histiocytosis. Lancet 1994;
343:767–768.
3. de Graaf JH, Egeler RM: New insights into the pathogenesis of
Langerhans cell histiocytosis. Curr Opin Pediatr 1997;9:46–50.
4. Egeler RM, Neglia JP, Puccetti DM, et al. Association of Lang-
erhans cell histiocytosis with malignant neoplasms. Cancer 1993;
71:865–873.
5. Egeler RM., Neglia JP, Aricò M, et al. Acute leukemia in asso-
ciation with Langerhans cell histiocytosis. Med Pediatr Oncol
1994;23:81–85.
6. Egeler RM, Neglia JP, Aricò M, et al. The relation of Langerhans
cell histiocytosis to acute leukemia, lymphomas, and other solid
tumors. The LCH-Malignancy Study Group of the Histiocyte So-
ciety. Hematol Oncol Clin North Am 1998;12:369–378.
7. Kager L, Heise A, Minkov M, et al. Occurrence of cute nonlym-
phoblastic leukemia in two girls after treatment of recurrent, dis-
seminated Langerhans cell histiocytosis. Pediatr Hematol Oncol
1999;16:251–256.
8. Fischer A, Jones L, Lowis SP. Concurrent Langerhans cell his-
tiocytosis and neuroblastoma. Med Pediatr Oncol 1999;32:223–
224.
9. Rosso D, Goldberg J, Balancini B, et al. Myelofibrosis in LCH.
Med Pediatr Oncol 1998;32:235.
10. Haas O, Gadner H. Pathogenesis, biology and management of
myelodysplastic syndromes in children. Semin Hematol 1996;33:
225–235.
11. Bennet JM, Catovsky D, Daniel MT, et al. Proposals for the
classification of myelodysplastic sydromes. Br J Haematol 1982;
51:189–199.
12. Brandwein JM, Horsman DE, Eaves CJ, et al. Childhood myelo-
dysplasia: suggested classification as myelodysplastic syndromes
based on laboratory and clinical findings. Am J Pediatr Hematol
Oncol 1990;12:63–70.
13. Hasle H. Myelodysplastic syndromes in childhood. Classification,
epidemiology and treatment. Leuk Lymphoma 1994;13:11–26.
LCH and Myelodysplasia 425
14. Hasle H, Aricò M, Basso G, et al. Myelodysplastic syndrome,
juvenile myelomonocytic leukemia, and acute myeloid leukemia
associated with complete or partial monosomy 7. European Work-
ing Group on MDS in childhood (EWOG-MDS). Leukemia 1999;
13:376–385.
15. D’Angio GJ, Favara BE, Ladisch S, et al. Workshop on the child-
hood histiocytosis: concepts and controversies. Med Pediatr Oncol
1986;14:104–117.
16. Ladisch S, Gadner H, Arico M, et al. LCH-I: a randomized trial of
etoposide vs. vinblastine in disseminated Langerhans cell histio-
cytosis. The Histiocyte Society. Med Pediatr Oncol 1994;23:107–
110.
17. Favara BE, Feller AC, Pauli M, et al. Contemporary classification
of histiocytic disorders. The WHO Committee on histiocytic/
reticulum cell proliferations. Reclassification Working Group of
the Histiocyte Society. Med Pediatr Oncol 1997;29:157–166.
18. Egeler RM, Favara BE, van Meurs M, et al. Differential in situ
cytokine profiles of langerhans-like cells and T cells in langerhans
cell histiocytosis: abundant expression of cytokine relevant to dis-
ease and treatment. Blood 1999 15;94:4195–4201.
19. Emile JF, Tartour E, Brugieres L, et al. Detection of GM-CSF in
the sera of children with Langerhans cell histiocytosis. Pediatr
Allerg Immunol 1994;5:162–163.
20. Rivera-Luna R, Alter-Molchadsky N, Cardenas-Cardos R, Mar-
tinez-Guerra G. Langerhans cell histiocytosis under 2 years of age.
Med Pediatr Oncol 1996;26:334–343.
21. Ladisch S. Histiocytosis. In: Willoughby MLN, Siegel SE, editors.
Hematology and oncology: Butterworth’s international medical
reviews. Pediatrics Vol 1. Woburn, MA: Buttherworth’s Scien-
tific; 1983. p 95–109.
22. Carstensen H, Ornvold K. The epidemiology of Langerhans cell
histiocytosis in children in Denmark, 1975–1989. Med Pediatr
Oncol 1993;21:387–388.
23. Ladisch S, Gadner H. Treatment of Langerhans cell histiocyto-
sis—evolution and current approaches. Br J Cancer 1994;
70(Suppl XXIII):S41–S46.