CLINICAL AND LABORATORY OBSERVATIONS

Asymptomatic Skeletal Cystic Angiomatosis May Be

Managed Conservatively With Close Observation
Waitman K. Aumann, MD, MS,*† Charles M. Maxfield, MD,‡
and Jessica L. Heath, MD§∥

lesions of the skull. Follow-up magnetic resonance imaging of the

Summary: Cystic angiomatosis (CA) is a rare disease characterized
by the proliferation of vascular and lymphatic channels lined by a
single layer of endothelial cells. CA may present with isolated
skeletal or visceral disease. There is no consensus for the standard of
care in these patients, and diverse regimens for CA have been
reported, including observation, surgery, radiation, and a variety of
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head revealed she had cystic lesions of the frontal, bilateral parietal,
and right occipital bones. Skeletal survey showed 4 mixed sclerotic
and lucent lesions in the skull, 1 in the medial right posterior fourth
rib, 1 in the right posterior-lateral fifth rib, and 1 in the left posterior
tenth rib, and bilateral proximal femurs. Computed tomography of
the chest abdomen and pelvis did not reveal visceral involvement

medical therapies. We present a case of multifocal, isolated skeletal but did show lytic lesions in T9, T10, and T11, as well as a lytic
CA, treated with close observation alone and review the literature. lesion in the pelvis at the left ilium.
We suggest that these cases may be safely followed without inter-
vention and may be stable for prolonged periods of time.
Key Words: cystic angiomatosis, lymphangiomatosis, pediatric
(J Pediatr Hematol Oncol 2020;00:000–000) A B

C ystic angiomatosis (CA) is an exceedingly rare disease

with <100 cases reported in the literature initially descri-
bed in the 1960s.1 Patients diagnosed with CA frequently
undergo imaging studies and biopsies to rule out formidable
diagnoses such as Gorham-Stout disease, malignancy, histio-
cytosis, or other lymphatic disorders.2 Typically, patients with
CA have multifocal bony lesions involving the axial and/or
appendicular skeleton.3 Patients may also have visceral C D
involvement including spleen, liver, mediastinum, or lungs.
Histologic examination reveals a proliferation of single-celled
endothelial lymphatic or vascular vessels.4 Although malignant
cells are not seen in this disease, progressive proliferation of
lymphatic and vascular channels in the bone and viscera can
be associated with significant and sometimes fatal complica-
tions. Treatment regimens have varied among reported cases,
and have included observation, bisphosphonates, propranolol,
steroids, alpha-interferon, surgery, and radiation therapy.5
However, when patients present with skeletal lesions only, the
decision to treat can be challenging, as outcomes can be E F
unpredictable, and many patients do not have progressive
disease. Here, we describe a pediatric case of incidentally
identified, asymptomatic, multifocal skeletal CA, and our
conservative management strategy.

CASE DESCRIPTION
A 12-year-old girl with no past medical history presented to
the emergency room after sustaining a fall at school. As part of the
evaluation, a head computed tomography showed multiple cystic

Received for publication August 7, 2019; accepted January 24, 2020.
From the *Aflac Cancer and Blood Disorders Center of Children’s
Healthcare of Atlanta; †Department of Pediatrics, Emory Uni-
versity, Atlanta, GA; ‡Department of Radiology, Duke University,
Durham, NC; §Department of Pediatrics, University of Vermont;
and ∥University of Vermont Cancer Center, Burlington, VT.
The authors declare no conflict of interest.
Reprints: Waitman K. Aumann, MD, MS, 1760 Haygood Drive, HSRB
W-355, Atlanta, GA 30322 (e-mail: waitman.aumann@emory.edu).
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 1. Magnetic resonance imaging findings of case-patient
at diagnosis and at 3-year follow-up. (A) Lesion in parietal bone
was 17.28 mm at diagnosis and at 3-year follow-up (B) lesion was
19.31 mm. (C) The lesion in T10 at diagnosis was 13.98 mm and
then at a 3-year follow-up (D) lesion was 14.11 mm. (E) The lesion
in the right femur at diagnosis was 26.61 mm and the right femur
was 18.38 mm, while at follow-up (F) right femur is 26.69 mm
and left femur was 24.07 mm. Variability in lesion sizes relates to
image capture.

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Aumann et al
TABLE 1. Review of Literature of Skeletal Cystic Angiomatosis
Patient Presenting to First Found Alive at Last Progression at Time of
Presentation References Age/Sex Medical Care Lesion Lesions Found Treatment Follow-up Last Follow-up Follow-up
Fracture Jacobs and 3/male Right elbow Unknown Humeri, femora, ribs, Supportive for Yes No 9y
Kimmelstiel15 fracture pelvis, scapula, skull fractures
Gramiak et al16 10/male Left femur Right humerus Skull, ribs, humeri, Supportive for Yes No 6y
fracture fracture verterbra, pelvis, fractures
femora
Toxey and 15/male Hand trauma Distal radius Metacarpals None Yes Yes Not
Achong17 on hand described
x-ray
Lateur et al18 31/male Right tibia Tibia x-ray Forearms, tibia, fibula None Not described Not described Not
fracture described
Goutoudi et al19 3/male Left femur Femur x-ray Skull, vertebra, pelvis, Supportive for Yes No 10 y
fracture humeri, femora, tibiae fractures
Discovered Reid et al20 35/female Fall on right Humerus Long bones of arms, legs, None Yes No 6 mo
incidentally after elbow and pelvis
orthopedic trauma
Reid et al20 21/male Fall on left knee Femur on knee Clavicle, long bones of None Yes No 10 y
x-ray arms and forearms,
small bones of hands,
long bones of legs
Cohen et al21 11/male Rib injury Chest x-ray Skull, pelvis, femora None Not described Not described Not
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described
Other medical Guttierez et al3 47/male Congestive heart Long bones, None None Died secondary to — —
findings failure found on medical reasons for
chest x-ray presentation

J Pediatr Hematol Oncol

Guttierez et al3 12/female Respiratory Right humerus Cranial vault, right None Yes No 3y
infection on chest humerus, pelvis,
x-ray femoral neck, left first
rib, right fifth rib
Schajowicz et al4 7/male Appendicitis Not described Pelvis, femora, several ribs None Yes No 2y
Marraoui et al22 58/male Pneumonia Left rib on Ribs and axial skeleton None Yes No 6 mo
chest x-ray


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These scans raised the suspicion for Langerhans cell histio-
cytosis. Pathology from a lesion of the frontal bone revealed mul-
tiple scattered dilated vascular channels, staining positive for CD34
and CD240. Focal areas of dilated lymphatic structures were also
observed, suggesting a lymphatic malformation. CD68 staining
revealed scattered histiocytes. Langerhans cell histiocytosis was
excluded based on negative staining for S100 and CD1a. She was
diagnosed, then, with CA.
She has since been followed with whole-body magnetic res-
onance imaging every 6 months for 3 years with no directed
therapy to these lesions. In the 3 years of follow-up, she has had no
evidence of progression of the known lesions, no development of
new lesions, and no development of visceral involvement (Fig. 1).
She continues to grow well, remain active in sports, and remains
asymptomatic.
DISCUSSION
Here, we describe a 12-year-old girl who presented with
incidental findings of lytic cranial lesions and was found to
have multifocal skeletal CA, without visceral involvement
following imaging and biopsy. Close monitoring over
4 years has revealed no further progression of the disease, in
the absence of therapeutic intervention.
CA is a heterogenous disease, with widely varying
presentation and clinical course, which has been recently
thoroughly reviewed by Najm et al.6 There is no consensus
for the treatment of CA, and previous reports have
described a variety of treatment modalities ranging from
observation to surgical intervention. Radiation therapy to
affected bones has been described in several case reports,
with some palliative effect on pain; however, the impact of
radiation on disease stability is difficult to assess, as this
disease is frequently static in nature.7–9 Bisphosphonates
have been the most frequently reported pharmacologic
treatment in CA, likely due to their utility in Gorham-
Stout disease, a similar, but more aggressive lymphangio-
matosis. In skeletal CA, bisphosphonate therapy has
shown mixed results, with 2 of 3 patients having stable
disease.5,6,9 Since the publication of these case reports,
guidelines regarding the use of bisphosphonates in children
have been released from the Australian Pediatric Endo-
crinology Group.10 While CA is not directly addressed,
these guidelines suggest that bisphosphate therapy maybe
consider in children with evidence of bone fragility, verte-
bral compression fractures, or progressive cystic bone dis-
ease, and provide guidance on dosing and monitoring.
Cellular therapy with autologous mesenchymal stem cells
was reported in a single patient and was not effective in
promoting bony healing.5 Denosumab, a monoclonal
antibody directed against RANK ligand, has been used in
the treatment of osteoporosis and was recently shown to be
effective in a series of 9 pediatric cases of the aneurysmal
bone cyst.11 It has not yet been used in CA. Sirolimus, an
mTOR inhibitor, has been studied prospectively in vas-
cular/lymphatic malformations with results showing a
decrease in size of the malformations; however, this study
only included patients who were grossly symptomatic and
no patients had CA.12 In addition, 2 recent systematic
reviews showed sirolimus to reduce the size of lymphatic
malformations.13,14 While none of these had CA, it is
possible that sirolimus has the potential to help
symptomatic patients.
There have been a total of 12 cases of skeletal CA
described in the literature, with initial presenting symptoms:
5 presented with a fracture, 3 with other orthopedic pre-
sentations, and 4 with other medical conditions where the
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Asymptomatic Skeletal Cystic Angiomatosis
lesions were incidentally found (Table 1). Seven of these cases
were found in pediatric patients. None of those patients
reportedly received CA directed therapy; 8 patients did well with
no progression of disease, 1 had rapid local progression of dis-
ease, although it is unknown the time to follow-up, 2 had no
follow-up information available, and 1 patient passed away
from his underlying medical condition for which he sought
initial medical care.
These case reports indicate that patients who are
diagnosed with skeletal CA following either a fracture or
other medical findings are likely at low risk for the devel-
opment of systemic disease or complications of the skeletal
disease. Given that the skeletal complications can include a
progression of the disease, pathologic fractures, debilitating
pain, and vertebral subluxation or dislocation, we propose
that close monitoring of asymptomatic pediatric patients
with skeletal CA, without visceral involvement, is safe and
feasible.
REFERENCES
1. Seckler SG, Rubin H, Rabinowitz JG. Systemic cystic angioma-
tosis. Am J Med. 1964;37:976–986.
2. Boyle WJ. Cystic angiomatosis of bone. A report of three cases
and review of the literature. J Bone Joint Surg Br. 1972;54:
626–636.
3. Gutierrez RM, Spjut HJ. Skeletal angiomatosis: report of three
cases and review of the literature. Clin Orthop Relat Res. 1972;
85:82–97.
4. Schajowicz F, Aiello CL, Francone MV, et al. Cystic
angiomatosis (hamartous haemolymphagiomatosis) of bone.
A clinicopathological study of three cases. J Bone Joint Surg Br.
1978;60:100–106.
5. Marcucci G, Masi L, Carossino AM, et al. Cystic bone
angiomatosis: a case report treated with aminobisphosphonates
and review of the literature. Calcif Tissue Int. 2013;93:462–471.
6. Najm A, Soltner-Neel E, Le Goff B, et al. Cystic angiomatosis,
a heterogeneous condition: four new cases and a literature
review. Medicine (Baltimore). 2016;95:e5213.
7. Clayer M. Skeletal angiomatosis in association with gastro-
intestinal angiodysplasia and paraproteinemia: a case report. J
Orthop Surg (Hong Kong). 2002;10:85–88.
8. Pavanello M, Piatelli G, Ravegnani M, et al. Cystic angioma-
tosis of the craniocervical junction associated with Chiari I
malformation: case report and review of the literature. Childs
Nerv Syst. 2007;23:697–700.
9. Shivaram GM, Pai RK, Ireland KB, et al. Temporal progression
of skeletal cystic angiomatosis. Skeletal Radiol. 2007;36:
1199–1204.
10. Simm PJ, Biggin A, Zacharin MR, et al. Consensus guidelines
on the use of bisphosphonate therapy in children and
adolescents. J Paediatr Child Health. 2018;54:223–233.
11. Kurucu N, Akyuz C, Ergen FB, et al. Denosumab treatment in
aneurysmal bone cyst: evaluation of nine cases. Pediatr Blood
Cancer. 2018;65:e26926.
12. Adams DM, Trenor CC III, Hammill AM, et al. Efficacy and
safety of sirolimus in the treatment of complicated vascular
anomalies. Pediatrics. 2016;137:e20153257.
13. Freixo C, Ferreira V, Martins J, et al. Efficacy and safety of
sirolimus in the treatment of vascular anomalies: a systematic
review. J Vasc Surg. 2020;71:318–327.
14. Wiegand S, Wichmann G, Dietz A. Treatment of lymphatic
malformations with the mTOR inhibitor sirolimus: a systematic
review. Lymphat Res Biol. 2018;16:330–339.
15. Jacobs JE, Kimmelstiel P. Cystic angiomatosis of the skeletal
system. J Bone Joint Surg Am. 1953;35-A:409–420.
16. Gramiak R, Ruiz G, Campeti FL. Cystic angiomatosis of bone.
Radiology. 1957;69:347–353.
|3 www.jpho-online.com
 Aumann et al J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2020

17. Toxey J, Achong DM. Skeletal angiomatosis limited to the
hand: radiographic and scintigraphic correlation. J Nucl Med.
1991;32:1912–1914.
18. Lateur L, Simoens CJ, Gryspeerdt S, et al. Skeletal cystic
angiomatosis. Skeletal Radiol. 1996;25:92–95.
19. Goutoudi PC, Sferopoulos NK, Papavasiliou V, et al. Cystic
angiomatosis of bone: a case report. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod. 1996;81:89–92.
20. Reid AB, Reid IL, Johnson G, et al. Familial diffuse
cystic angiomatosis of bone. Clin Orthop Relat Res. 1989:
211–218.
21. Cohen MD, Rougraff B, Faught P. Cystic angiomatosis of
bone: MR findings. Pediatr Radiol. 1994;24:256–257.
22. Marraoui W, Michel JL, Kemeny JL, et al. Imaging features of
systemic cystic angiomatosis. Diagn Interv Imaging. 2015;96:
1211–1213.

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