Article

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

Service d'hématologie oncologie pédiatrique, Centre de référence des histiocytoses, AP-HP Hôpital Armand Trousseau, Paris, France.
Orphanet Journal of Rare Diseases (Impact Factor: 3.36). 02/2010; 5(1):3. DOI: 10.1186/1750-1172-5-3
Source: PubMed
ABSTRACT
To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children.
Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.
21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications.
Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.

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RESEA R C H Open Access
Retrospective French nationwide survey of
childhood aggressive vascular anomalies of bone,
1988-2009
Sébastien Héritier
1*
, Martine Le Merrer
2
, Francis Jaubert
3
, Michèle Bigorre
4
, Marion Gillibert-Yvert
5
,
Benoit de Courtivron
5
, Makram Ziade
4
, Yves Bertrand
6
, Christian Carrie
7
, Pascal Chastagner
8
, Cécile Bost-Bru
9
,
Jean-Claude Léonard
10
, Marie Ouache
11
, Liliane Boccon-Gibod
12
, Pierre Mary
13
, Jacques de Blic
14
, Isabelle Pin
9
,
Daniel Wendling
15
, Yann Revillon
16
, Véronique Houdoin
14
, Véronique Forin
17
, Hubert Ducou Lepointe
18
,
Jane Languepin
19
, Jeanne Wagnon
20
, Ralph Epaud
21
, Brigitte Fauroux
21
, Jean Donadieu
1
Abstract
Objective: To document the epidemiological, clinical, histological and radiological characteristics of aggressive
vascular abnormalities of bone in children.
Study design: Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of
aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.
Results: 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease
appeared to be sporadic. Mean age at di agnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-
17 years]. The main prese nting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent
onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most
frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used
as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused
major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact
on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions
was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths
were observed and the over all 10-year mortality rate was about 30%. The prognosis depended mainly on
pulmonary and spinal complications.
Conclusion: Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The
impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone
lesions.
Introduction
Aggressive vascular abnormalities of bone consist of
intra-osseous vascular abnormalities leading to osteolysis
and, sometimes, extension to ad jacent tissues [1]. These
diseases are very rare, and affect children and young
adults [2]. They may be disseminated or focal, but both
forms can be very ag gressive and life-threatening. These
bone vascular abnormalities are distinct from malignant
bone tumors with vascular proliferation, such as angio-
sarcoma and hemangio endothelioma [3]. In the litera-
ture, such entities are variously named disseminated
cystic bone angiomatosis (mostly multifocal) [4] and
aggressive massive osteolysis [5] (also called Gorham-
Stout disease if unifocal). Some authors use the name
Gorham-Stout disease for multifocal cystic bone angio-
matosis [6-12], and nearly ten other names have also
been used. A recent review of 43 cases of vascular
lesions of b one recommended the use of the ISSVA
classification [3].
* Correspondence: heritier.sebastien@yahoo.fr
1
Service dhématologie oncologie pédiatrique, Centre de référence des
histiocytoses, AP-HP Hôpital Armand Trousseau, Paris, France
Héritier et al. Orphanet Journal of Rare Diseases 2010, 5:3
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Page 1
The natural history of such diseases is mainly known
through individual case reports, and there are only two
series wit h more than 10 patients (15 and 11 cases)
[13,14]. The lack of e pidemi ological data, togethe r with
the con flicting nature of available information, especially
on the natura l history and patient managemen t, led us
to conduct a retrospective study of cases diagnosed in
France during the past 21 years. Here we report the epi-
demiological, clinical and biological characteristics,
treatment modalities and outcome.
Patients and Methods
All children (age <18 years at diagnosis) with a diagnosis
of aggressive vascular abnormalities o f bone (incl uding
bone angiomatosis and Gorham-Stout disease )
between 1 January 1988 and 1 September 2009 and
managed in a French hospital were eligible for the
study. We contacted all pediatricians belonging to the
Society of Pediatric Hematology-Immunology and the
French Pediatric Cancer Soci ety, including orthopedic
surgeons in French teaching hospitals. The diagnosis of
aggressive va scular abnormalities of bone was based on
histological examination of a bone lesion. A presumptive
diagnosis could be made in th e following circumstances:
Situation A: bone osteolysis and chylous pleural effu-
sion, with o r without pulmonary lymphatic infiltration;
and situation B: isolated bone osteolysis, provided Lan-
gerhans histiocytosis and infectious bone abscess were
rul ed out. In thi s latt er case the diagnosis was based on
three criteria: 1) the site of involvement (vertebra, ribs,
pelvis and scapular belts); 2) few if any bone symptoms,
in the absence of complications (fracture, including ver-
tebral collapse); and 3) the following characteristic
aspect on roentgenography or magnetic resonance ima-
ging (MRI): well-defined piecemeal lesions; centrome-
dullary and cortical involvement with no periosteal
reaction; pseudocystic aspect and ring-shaped peripheral
contrast uptake with secondary filling. In the absence of
histological documentation, patients with osteolysis
involving solely t he feet and hands, and patients with
associated renal dise ase [15], were excluded, as were
patients with isolated pulmonary chylothorax and
lymphangiectasis.
Multifocal osseous forms are defined as those in
which osteolysis affects several bone segments distant
from one another, with healthy bone in-between. Loca-
lized osseous forms are defined as those in which osteo-
lysis affects only one bone with contiguous lesions, or
several anatomically contiguous bones.
The date of diagnosis was the date of biopsy when
relevant. For presumptive diagnoses, the date of diagno-
sis was the date of X-ray examination showing typical
lesions. The date of first symptoms was the date when
the first manifestations potentially related to the disease
were reported by the patie nt or the family. Clinical
remission is defined as the absence of any co mplication
for at least two years. The following criteria were used
to e valuate therapeutic efficacy: i) symptomatic lesions
(dyspnea due to pulmonary involvement, clinically asses-
sable cutaneous, subcutaneous or soft-tissue involve-
ment): efficacy was judged at 3 months, based on
changes in respiratory status or stabilization of lesion
volume; ii) in the absence of symptomatic lesions (solely
radiological signs of bone involvement or asymptomatic
involvement of a deep organ [spleen]), efficacy was
judged at 2 years, base d on the occurrence of complica-
tions. Complications were defined as follows: bo ne frac-
tures; vertebral collapse; consequences of tissue
destruction due to proliferation of pathological tissue
and n ecessitating hospitalization; a nd all other serious
complications. Serious complications included dissemi-
nated intravascular coagulation; respiratory failure due
to pl eural effusion, or lung lymphangiectasis and v erteb-
ral collapse with neurological complications.
The following data were systematically collected from
the patients files: clinical information, i.e. personal and
family history, symptoms; histology; biology; and ima-
ging studies (including radiography of the lesions, M RI,
scintigraphy, and bone densitometry). Treatments and
complications were recordedfromdiagnosistothelast
visit. No further examinations were requested for this
solely observational study. Cases #10, #12 and #13 have
been partially reported elsewhere [16-18]. The Kaplan-
Meier method was used to estimate survival rates. The
endpoint for the survival analysis was death. The period
taken into account was the interval between the date of
diagnosis and the e vent (or the last examination when
no event occurred). The c ut-off date was 15 September
2009.
Results
Characteristics of the patients
There were 8 girls and 13 boys Table S1, Additional file
1. Two children originated from North Africa (including
a French resid ent), one was from Italy, and the other 18
children were of French origin. No parental consangui-
nity was found, and there was no known family history
of aggressive vascular abnormalities of bone, or ot her
vascular abnormalities. Patient #1 had had a heman-
gioma during infancy that regressed spontaneously. Two
children were born prematurely (30 and 34 weeks).
Patient #18 had a dominant form of fami lial exostosis,
as did his mother. This patient was mentally retarded
and ha d had three severe bacterial infections (pneumo-
coccal meningitis, o steomyelitis due to betahemolytic
streptococci, and Staphylococcus aureus pneumonia).
Patient #12 was also mentally retarded and patient #7
had partial epilepsy.
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Mean age at diagnosis was 8.0 years [0.8 to 16.9
years]. N o clear triggering factors were identified. Two
patients had suffere d trauma close to the affected areas,
more than two years pre viously. Four other patients had
had infections in the region of the affected areas: patient
#16 contrac ted mumps less tha n two months before
onset, which was revealed by laterocervical tumefaction;
patient #10 had had pleurisy and pneumococcal puru-
lent pe ricarditis at age 4 years (9 ye ars before the d iag-
nosis of thoracic angiomatosis); patient #18 had had
bilateral lymphatic pleural effusion after an episode of
pneumonia associated with Staphylococcus aureus bac-
teremia; patient #3 had recurrent purulent meningitis
(due to Haemophilus influenzae), revealing a mening eal
defect at the third episode, leading to the diagnosis of
aggressive vascular abnormalities of bone.
Diagnosis and clinical manifestations
Pathological examination confirmed the diagnosis in 16
cases, on a sample of a bone lesion in 15 cases and of
involved skin and spleen tissue in a patient with bone
lesions. In three cases (#1, #3 and #7), a second biopsy
was required for diagnosis. In case #9 an aggressive vas-
cular abnormality o f bone was diagnosed after re-exam-
ining the initial specimen, 6 years after misdiagnosis of
Langerhans histiocytosis. In case #4 and #20 the only
bone biopsy was non co ntributo ry. In cases #8 and #11,
two biopsy procedures were complicated by heavy
bleeding (including a case of pulmonary hemorrhage)
and t he diagnosis remained presumptive. These two
cases were diagnosed on the basis of a combination of
typical bone lesions and pleural effusion or lymphan-
giectasis on pulmonary CT, corresponding to presump-
tive diagnosis (situation A). In cases #2, #4 and #20 the
diagnosis remained presumptive (situation B).
The median interval between the first clinical manifes-
tations and the diagnosis of aggressive vascular abnorm-
alities of bone , assessable in 1 8 patients, was 0.47 years
(range 0.01-10.3 years). In nine cases, at least 6 months
elapsed between the discovery of osteolysis and the diag-
nosis of aggressive vascular abnormalities of bone. Three
patients initially received specific chemotherapy (vinblas-
tine and steroids) for suspected Langerhans histiocytosis,
to no effect. The first sign of the disease was an acute
complication in 13 of the 21 patients , cons isting o f
pathological fractures (n = 4), cyphosis due to vertebral
collapse (n = 1), dyspnea (n = 7) due to abundant
pleural effusion (n = 5) or to respiratory failure with
pulmonary lymphangiectasis (n = 2), or meningitis due
to an osteomeningeal breach (n = 1) [Table S1, A ddi-
tional file 1]. One case was revealed by chronic lumbo-
sacral pain and one by a persistent limp, while one case
was diagnosed during investigation of chronic lumbago
associated with growth retarda tion. Three patients pre-
sented with subcutaneous tumefaction and one case was
diagnosed at age 7 years, during f ollow-up of a cervical
lymphangioma, diagnosed at birth, which relapsed once
at age 2 years and was then complicated by spleen
involvement; later radiographs showed vertebral, scapu-
lar and iliac lesions. Finally, in one case the disease was
diagnosed on radiographs prescribed for facial trauma
following a vagal malaise.
Extension
The two most frequently affected bone sites were the
spine (16 cases, especially the dorsal spine), and the ribs
(12 cases). The other sites, in order of decreasing fre-
quency, were the pelvis, cranium, femur and humerus.
Sixteen patients had multifocal osseous forms at diag-
nosis. Six patients ha d more that 9 affe cted bone seg-
ments, including a child wi th 13 sites (case #6) [Table
S1, Add itional file 1]. Five patients had localized forms:
two h ad lesions localized to the pelvis and lower limbs
(cases #2 and #5) while the other three had lesions loca-
lized to the thoracic cage (ribs, dorsal spine and ster-
num; cases #10, 12 and #13).
Extraosseous involvement was observed in 18 cases
[Table S1, Additional file 1], usually at diagnosis. Pul-
monary involvement occurred in 10 children: 9 children
had pleural effusions (figure 1) composed of bloody
fluid (n = 1), chylous fluid (n = 5) or initially hemorrha-
gic then chylous fluid (n = 1); in two cases the nature of
the ef fusion was not determined. In f ive pa tients (# 8,
#10, #15, #18, #19) the pleural effusion was associated
with pulmonary lymphangiectasies characterized radiolo-
gicallybyadiffuseinterstitial syndrome (figure 2).
Finally, one patient (#9) had a radiological interstitial
syndrome related to pulmonary lymphangiectasies, but
remained asymptomatic. Spleen involvement was diag-
nosed in 8 children and was always asymptomatic. The
diagnosis was made on routine abdominal sonography
showing cystic lesions. Cutaneous or subcutaneous
involvement was reported in 7 cases. Patient #14 was
found to have urinary bladder involvement at autopsy.
Finall y, ma ny patients had sof t tissue involvement close
to their bone lesions, and patients #10 and #15 had
extension to the mediastinum or peritoneum.
Among the five patients with localized forms, the
three who had lesions localized to the thoracic cage
developed lung involvement.
Imaging and laboratory findings
Patients with multifocal osseous forms had rounded
well-defined radiolucent bone lesions on imaging studies
(figure 3). Rib involve ment gave a puffy as pect to the
cortical bone (figure 1), which was very similar in the
five relevant cases (#1, #7, #9, #13, #15). MRI findings
consisted of well-defined bone lesions that were T1
hypointense and T2 hyper intense (fi gure 4) and took up
contrast medium, giving an aspect of cystic bone lesions.
In 10 of the 11 cases in which the bone matrix was
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Page 3
studied, the aspect was one of a gen eral decrease in ske-
letal bone density, confi rmed by bone densitome try ( 3
SD). Technetium scintigraphy (n = 7) f ailed to detect
the bone lesions a nd was far less s ensitive than MRI,
bone scan or radio graphs. Regarding bio logical findings,
only patient #18 had an inflammatory syndrome. The
water-electrolyte bal ance and hepatic biochemistry were
normal in all the patients. Five patients (cases #8, #10 #
11 #18 and #19) had biological signs of disseminated
intravascular c oagulation (DIVC). These five patients
had concurrent progressive pulmonary involvement
(symptomatic pulmonary lymphangi ectasis in two case s,
and pleural effusion in three cases). Patient #18 had
lymphopenia (between 400 and 600/mm
3
) without hypo-
gammaglobulinemia, No immune deficiency was
observed in the three patients who i nitially presented
with a bacterial infection.
Pathological findings
Pathological specimens were reviewed in 7 cases (figure
5 and 6). Bone specimen (humerus, femur, scapula and
skull) were recovered. The humerus and scapula speci-
mens showed endothelialized sinusoids replacing the
bone, with no oste ogenesis and disappearance of the
bone marrow. A small femur biopsy showed a focus of
osteoclastic hyperactivity and the skull specimen
included the wall of an endotheliform c avity. Lung and
pleural specimens were available in two cases and
showed numero us abnormal lymphatic cavities with
accompanying smooth muscle bundles. Skin b iopsy was
done in one case and showed an hypodermic focus of
aggr egated lymphatic cavities with som e smooth muscle
differentiation. A spleen specimen was available in one
case and showed a network of e ndothelialized sinusoids
lined by some smooth muscle bundles. Immunohisto-
chemistry was done and showed D2-40 positivity of the
endothelial lining, and a continuous CD31 positive lin-
ing of the spleen cavities.
Therapeutic management
In addition to symptomatic treatments, three therapeutic
approaches were attempted, namely radiotherapy, cyto-
static drugs (including vinca alka loids and ster oids), and
antiangiogenic drugs (a interferon, bisphosphonates,
thalidomide and bevaci zumab) [Table S2, Additional file
1]. Treatment was tailored to the individual patients.
We analyzed treatment efficacy according to the affected
organs, as each site of involvement presents different
targets and therefore different methods of assessment.
Management of patients with symptomatic pul monary
involvement (n = 9) consisted of routine pleural drai-
nage, with octreotide infusion in 4 cases a nd surgical
shunting in 3 cases. In one case (case #13) drainage
alone was sufficient to prevent further relapses. Various
curative treatments were attempted in refractory forms:
radiotherapy of the chest wall or a lung half-field (n =
4), chemotherapy with vinca alkaloids (vincristine a nd
vinblastin) (n = 3), and interferon alfa, with or without a
bisphosphonate or thalidomide (n = 4) and finally bev a-
cizumab in one case. Pleural radiotherapy was adminis-
tered at individually tailored doses. Four cases of pleural
effusion were treated with chest irradiation at doses of
49.5 Gy in case # 12 (unilateral),18Gy(right)+12Gy
(left) in case #11, 18 Gy in c ase #8 (unilateral) and 8.5
Gy in case #14 (unila teral). The three p atients treated
with the highest doses have had no recurrent effusion
during more than 8 years of follow-up, but they have
severe orthopedic sequelae. Patient #8, after a marked
clinical improvement at 6 months, remained stable until
the recurrence of pleural effusion with intrapulmonary
lymphangiectasis 8 years later, but the pleural effusion
relapsed at this time. This relapse was refractory to a
combination of a interferon and thalidomide. The
patient treated with a lower dose (8.5 Gy) died within
two months, with no improvement in the pleural effu-
sion. Two patients were treated with vinca alkaloids
(vincristine (n = 2 ) and vinblastine (n = 1); at least six
injections), combined with oral steroids (40 mg/m
2
/d for
4 weeks). No improvement was observed in either case.
Four p atie nts received a interferon, one in combination
with zoledronate, one in combination w ith pamidronate
and one in combination with thalidomide. The patient
treated with a interferon alone (case #15) had syste mic
toxicity, leading to treatment withdr awal after 83 days
with no improvement. The patient treated with a
Figure 1 Pulmona ry inv olvement: pleural effusion associat ed
with pulmonary lymphangiectasies (case #15) (White arrow:
puffy aspect of costal cortical bone).
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interferon and pamidronate (case #19) showed no
improvement. The patient treated with a interferon and
thalidomi de (case #8) was refr actory and died at month
2. Finally, only the patient (case #18) treated with a
interferon and zoledronate showed an improvement in
pleural effusion, at month 3, but the pleural effusion
relapsed at month 9 and was not sensitive to
bevacizumab.
Management of seven patients w ith skin an d subcuta-
neous lesions or subcutaneous tumor was also very
diverse. Three patients received radiotherapy. In pa tient
#11, a subcutaneous lesion of the left hemithorax
disappeared after 6 months of radiotherapy (12 Gy) pre-
scribed for pleural effusion, while patient #14 and #15
showed no improvement following 8.5 Gy and 15 Gy.
One patient (#9) received the standard treatment for
Langerhans histiocytosis (12 injections of vinblastine
and steroids 40 mg/m
2
) for 6 months, to no effect. Two
patients were treated with a interferon alone: Patient
#15 was treated for 83 days with no measurable effect,
and patient #16 was treated f or at least 3 months and
had no measurable improvement. Two patients received
a bisphosphonate, with or without a interferon: Patient
#4 (treated with zoledronate 0.05 mg/kg IV every 3
months) had no measurable improvement. Patient #9
was treated with etidronate (400 mg/d) and a interferon
(2.5 × 10
6
U/m
2
three times a week), and the supraclavi-
cular and cervical extension appeared to remain stable
during 9 months of follow-up.
Involved bone was a target of systemic treatments in
10 patients but the short-term response was difficult to
assess because it was usually asympto matic, except in
case of fracture. In addition to local treatments, only a
interferon and/or bisphosphonates were tried in these
ten cases. In seven cases (#2, #3, #4, #9, #18, #19, #20)
no bone complications have occurred, but these patients
have less than two years of follow-up. In patient #1,
treated with a inte rferon (1. 5 × 10
6
U five times a week
then tapered to three times a week) secondarily com-
bined with pamidronate, no bone complications have
occurred with more than two years of follow-up. Finally,
new fractures occurred during long-term pamidronate
therapy in patient #6 and during long-term pamidro-
nate/zoledronate and a interferon in patient #7.
Embolization (case #13) and sclerotherapy (case #16
and #17) were also attempted in three cases but only
patient #17 showed an improvement. Surgery aimed at
resecting all angiomatous tissue was never attempted in
this series.
Complications, outcome and prognosis
The disease progressed either gradually or discontinu-
ously, with periods of stabilization and symptom disap-
pearance followed by new complications. However, it
was diff icult to identify disease progression formally, as
regular evaluations were not performed.
Nine patients ha d respiratory complications leading to
respiratory distre ss, which was fat al in five cases.
Respiratory distress was secondary to pleural effusion or
to an exacerbation of pulmonary lymphangiectasis.
Spinal complications, including vertebral collapse,
occurred in 10 patients. They were generally mild but
were a ccompanied by spinal cord damage in two cases,
with one death by cervical cord section and one case of
permanent paraplegia. Pathological fractures occurred in
8 patients. Finally, one patient had r ecurrent meningitis
due to an osteomeningeal breach secondary to skull
Figure 2 Lung CT scan (case #8) showing lymphangiectasies.
Figure 3 Skull radiography with rounded well-defined
radiolucent bone lesions (case #15).
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base involvement. Biological signs of disseminated intra-
vascular coagulation were observed in five cases and
lasted several months.
Six patients died (29%). The survival rate 10 years
after o nset was 71% (95%CI 43-87%) but the curve has
not yet plateaued. The six deaths occurred between 3
months and 16.9 years after onset (median 2.4 years).
The causes of death were pulmonary involvement (5
cases) and spinal involvement (1 case).
Four patients are in persistent clinical remission, with
an active phase of 1 year (#11), 4 years (#12), 10 years
(#7) and 13 years (#13). Three of th e four patients in
remission have severe sequelae, consisting of radiother-
apy-induced scoliosis in two cases and paraplegia sec-
ondary to vertebral collapse in one case.
Discussion
This retrospective survey identified 21 cases of aggres-
sive vascular abnormal ities of bone i n children over a
21-year period in France. Despite the small number of
cases, this is the large st pediatric series published to
date. We used a national network of specialists in pedia-
tric hematology-oncology and including pediatric ortho-
pedists, as most patients present with what resembles a
bone tumor and are thus referred to such specialists.
AlthoughwecannotbesureweidentifiedallFrench
cases, it is unlikely that the true number o f cases was
much higher, and the prevalence of the disease probably
corresponds to t hat of extremely rare conditions, i.e.
between 0.1 and 1 case per million children less than 15
years of age. There was a male predominance in our
series, as reported in the literature [2,14]. We found no
familial cases and no consanguinity. No intercurrent dis-
orders were present in 20 of t he 21 patients. The asso-
ciation with dominant familial exostosis is noteworthy,
even if no clear link has been found between the two
disorders. The diagnosis of the disease in 3 cases after
bacterial infections of the same serous membra ne is
intriguing, but no conclusion can be drawn from this
observation alone. Most patients presented with
Figure 4 Whole body coro nal and sagittal MRI (case #20). T2-weighted MRI of spinal (C2; C3; C6®T10; L1), costal, left s capular and left
femoral lesions.
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symptoms linked to bone lesions (fractures) or to pul-
monary involvement. In three cases the initial diagnosis
was Langerhans histiocytosis a nd the patients recei ved
the relevant treatment before the diagnosis was cor-
rected (notably in view of the lack of therapeutic
efficacy).
This series comprised multifocal forms with cystic
intraosseous lesions seen on imaging studies (n = 16),
and localized forms (n = 5), corresponding to the two
previously identified forms of « osseous angiomatosis »,
namely multifocal cystic osseous angiomatosis for multi-
focal f orms and aggressive massive osteolysis ( aka Gor-
ham-Stout disease) for unifocal forms. Careful appraisal
of the p atients medical history and imagery shows,
however, that there is no clear basis for the distinctio n
between these two forms. The 5 patients initially consid-
ered as having localized disease resembled the patients
with multifocal forms, with respect to demographic
characteristics and outcome (especially secondary pul-
monary extension and mortality). One of our patients
(case #14) was considered to have localized invol vement
(thoracic cage), complicated by pleural e ffusion, but
autopsy revealed the presence of abnormal v ascular
tissues in the skull and pelvis and urinary bladder.
Moreover, not all the patients had radiographic studies
of the entire skeleton, as in some localized fo rms
reported in the literature. Th us, in the abse nce of pre-
cise biolog ical, pathological or even radiolog ical criteria,
we suggest tha t all patients should be considered to
belong to a single nosologic entity. In future studies of
aggressive vascular malformations of bone, the diagnos-
tic work-up should systemically include all bones and
lung CT.
Diffuse bone demine ralization was observed in t en of
the eleven assessable cases. This phenomenon has also
been reported in the literature [19] and supports the
current view that the osteolysis is related to osteoclast
hyperstimulation [15,20,21].
Pathological specimens were reviewed in 7 cases. The
bone lesions were composed of abnormal non fene-
strated sinusoids with continuous wall CD31 positivity.
Lung lesions showed subpleural and peribronchial
dilat ed lymphatic cavit ies, sometimes wit h smooth mus-
cle bundles in the walls. Spleen lesions showed dissemi-
nated cystic cavities of non fenestrated CD31-positive
sinusoids with surrounding smooth muscle. Skin lesions
Figure 5 Pathological findings: Hematopoietic locations. A: Capillari zed sinusoids of a bone biopsy with an inflammatory surrounding (HES
×400). B: CD31 positivity of the endothelial lining of capillarized sinusoids (×200). C: Spleen dilated sinusoids (smooth muscle actin ×100). D:
Spleen larger cysts lined by a continuous layer of CD31 endothelial cells (CD31 × 100).
Héritier et al. Orphanet Journal of Rare Diseases 2010, 5:3
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Page 7 of 10
Page 7
were mainly hypodermic, with foci of cystic lymphatic
D2-40 positive and venula CD31 positive abnormal
aggregation. In summary, aggressive vascular ab normal-
ities of bone lesions mainly consisted of capillarized
sinusoids i n bone marrow and spleen and abnormal
lymphatics with smooth muscle lining in lung, pleura
and s kin. A recent study sho wed that these capillarized
sinusoids a re CD 105 (endoglin)-positive, like the bone
of growth plate capillaries [22]. Among aggressive vascu-
lar abnormalities of bone, it is difficult to distinguish
between venous and lymphatic subtypes, as suggested in
Bruders recent review article [3]. Likewise, the literature
contains numerous borderline forms between predomi-
nantly venous and predominantly lymphatic forms.
Immunohistochemical studies, especially those focusing
on CD31 (an endothelial marker), CD34 (expressed b y
blood vascular endothelial cells), D2-40 and LYVE-1
(lymphatic endothalial cells), markers of vascular prolif-
eration such as the MIB1 prolife rative index and VEGF
expression within the lesions, would appear to be more
useful for subdividing, or on the contrary uniting, these
pathological entities. We recommend grouping together
these disorders under the term « aggressive vascular
abnormalities of bone », instead of the older term «
angiomatosis of bone», as the « oma » suffix is sugges-
tive of tumor proliferation.
In t his study, neither chemotherapy wit h spindle poi-
sons nor steroid therapy at a dose of 40 mg/m
2
was
beneficial. Thirteen patients received a interferon (n =
8) and/or bisphosphonates (n = 10). Only six cases trea-
ted with a interferon, associated with bisphosphonates
in 3 cases, have been reporte d in the literature [Table
Figure 6 Pathological findings: Lung locations. A: Peribronchiolar dilated lymphatics (HES × 400). B: Foci of smooth muscle actin positivity
alongside dilated lymphatic (SMA × 200). C: Parietal biopsy at low magnification showing its thickening, with numerous lymphatic cavities and
inflammation (HES × 100). D: Higher magnification of the D2-40 lining of vascular cavities with some smooth muscle bundles in between (SMA
× 200).
Héritier et al. Orphanet Journal of Rare Diseases 2010, 5:3
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Page 8 of 10
Page 8
S3, Additional file 1] [9,10,23-26]. We observed only
short-term efficacy in one patient with pleural effusion
(#18), whereas the literature describes four cases of suc-
cessful treatment and one failure [Table S3, Additional
file 1]. The value of a interferon-bisphosphonates com-
binationsinthissettingremainstobedetermined.
These treatments, especially after prolonged administra-
tion, appeared more effective for preventing bone com-
plication and limiting the osteolytic process, as observed
in two cases (#1 and #7), but the other cases have insuf-
ficient follow-up. Currently, there is no clinical basi s on
which to choose a particular bisphosphonate.
High-dose thoracic radiothera py (at least 18 Gy) had a
durable impact on pleural effusions, but two children
thus treated developed severely incapacitating scoliosis
and a relapse was observed in 1 of 3 c ases after 8 years.
In contrast, a dose of 8.5 G y was not effective. Thus, it
seems that high doses must be used in this setting.
Indeed, other authors have recommended doses between
25 and 45 Gy [27-30]. Fractionated bone radiotherapy at
a total dose of 25 to 40 Gy can stop the osteolytic pro-
cess [31-34], but failures have also been published
[2,23,35,36]. None of our patients underwent surgery
aimed at resecting all the vascular abnorm al tissue. Sur-
gical treatments had variable results, and bone grafts
during the active phase of the disease have a tendency
to be resorbed [11,31,37].
In our series the vital prognosis depended on pulmon-
ary and spinal involvement. Spec ial attention must be
paid to localized forms affecting the thoracic cage, as
they carry a high risk of pulmonary complications. Pul-
monary complications such as pleural effusion have
already been reported i n the literature, with an esti-
mated incidence of between 17% and 25% [9,38]. In
contrast, 47% of our patients presented with radio-
graphic and/or clinical signs of pulmonary lymphangiec-
tasis or pleural effusion. We observed five cases of
pulmonary lymphangiectasis, characterized in four ca ses
by respiratory failure and associated with pleural effu-
sion; no clinical manifestations occurred in the last case.
Conclusion
Aggressive vascular abnormalities of bone are rare but
potentially l ife-threatening disorders of unknown etiol-
ogy. Localized forms a nd multifocal cystic bone forms
are very similar, and there seems to be no reason to
consider them as distinct en tities. Pulmonary involve-
ment is a major prognostic factor. The efficacy of anti-
angiogenic treatments and of third- generation
bisphosphonates such as zoledronate is unclear and
must be further evaluated. Molecular biology-based
approaches, including immunolabelling of bone lesion
samples, should help to understand these disorders and
to orient the choice of treatment.
Additional file 1: Table S1, Table S2, Table S3. Table S1 - Disease
presentation - mean features of 21 patients with aggressive vascular
abnormalities of bone. Table S2 - Therapeutic management and
outcome of 21 patients with aggressive vascular abnormalities of bone.
Table S3 - Summary of the literature on a interferon and/or
bisphosphonate therapy in aggressive vascular abnormalities of bone
Click here for file
[ http://www.biomedcentral.com/content/supplementary/1750-1172-5-3-
S1.DOC ]
Acknowledgements
The authors thank David Young for editorial assistance and the French
Histiocytosis Association. This study was supported by grants from Groupe
détude des histiocytoses, and the Histiocytosis Reference Center. We also
thank the patients and their families for their participation in this study, and
Mr J.P. Grignet and Ms D. Sommelet.
Author details
1
Service dhématologie oncologie pédiatrique, Centre de référence des
histiocytoses, AP-HP Hôpital Armand Trousseau, Paris, France.
2
Service de
génétique, Centre de référence des maladies osseuses, AP-HP Hôpital
Necker, Paris, France.
3
Service danatomie et cytologie pathologique, AP-HP
Hôpital Necker, Paris, France.
4
Service de chirurgie plastique pédiatrique,
Hôpital Lapeyronie, Montpellier, France.
5
Service dorthopédie, Hôpital
Clocheville, CHU de Tours, France.
6
Institut dhématologie et doncologie
Pédiatrique, Lyon, France.
7
Département de radiothérapie, Centre Léon
Bérard, Lyon, France.
8
Service de Médecine Infantile, Hôpitaux de Brabois,
Vandoeuvre les Nancy, France.
9
Pédiatrie, Pôle Couple enfant, CHU de
Grenoble, France.
10
Institut Calot, Berck sur Mer, France.
11
Service
dhématologie, AP-HP Hôpital Robert Debré, Paris, France.
12
Service
danatomie et cytologie pathologique, AP-HP Hôpital Armand Trousseau,
Paris, France.
13
Service dorthopédie, AP-HP Hôpital Armand Trousseau, Paris,
France.
14
Service de pneumologie, AP-HP Hôpital Necker, Paris, France.
15
Service de rhumatologie, CHU de Besançon, France.
16
Service de chirurgie
viscérale, AP-HP Hôpital Necker, Paris, France.
17
Service de rééducation,
Centre de référence des maladies osseuses, AP-HP Hôpital Armand
Trousseau, Paris, France.
18
Service de radiologie, AP-HP Hôpital Armand
Trousseau, Paris, France.
19
Service de pédiatrie générale, CHU de Limoges,
France.
20
Service de pédiatrie générale, CH de Morlaix, France.
21
Service de
pneumologie, Centre de référence des maladies pulmonaires rares, AP-HP
Hôpital Armand Trousseau, Paris, France.
Authors contributions
The study was designed by SH and JD. Data management was coordinated
in France by SH. MLM, FJ, MB, MGY, BC, MZ, YB, CC, PC, CBB, JCL, MQ, LBG,
PM, JB, IP, DW, YR, VH, VF, HDL, JL, JW, RE, BF, and JD were responsible for
patient management. The manuscript was written and approved by all the
coauthors.
Competing interests
The authors declare that they have no competing interests.
Received: 17 October 2009
Accepted: 3 February 2010 Published: 3 February 2010
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doi:10.1186/1750-1172-5-3
Cite this article as: Héritier et al.: Retrospective French nationwide
survey of childhood aggressive vascular anomalies of bone, 1988-2009.
Orphanet Journal of Rare Diseases 2010 5:3.
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