Skeletal Radiol (2007) 36:1199–1204
DOI 10.1007/s00256-007-0378-3
CASE REPORT
Temporal progression of skeletal cystic angiomatosis
Giridhar M. Shivaram & Reetesh K. Pai &
Kevin B. Ireland & Kathryn J. Stevens
Received: 16 April 2007 / Revised: 31 July 2007 / Accepted: 14 August 2007 / Published online: 3 October 2007
# ISS 2007
Abstract Cystic angiomatosis is a rare, benign, multifocal
disorder of bone and viscera, in which angiomatous
deposits of both vascular and lymphatic elements result in
bone lysis and organ dysfunction. We report on a case of
late-onset cystic angiomatosis in a Caucasian woman who
first presented at age 35 years with a lytic expansile lesion
of the proximal humerus, initially diagnosed as low-grade
hemangio-endothelioma. This was treated with injection of
cement and prophylactic pinning. However, the lesion
continued to grow, and, 5 years later, she was discovered
to have disseminated bony involvement, initially thought to
represent metastatic disease. However, further investigation
revealed a diagnosis of cystic angiomatosis, and the patient
was treated with bisphosphonates. Follow-up over a 15-
year period since her initial presentation at age 35 years has
shown osteosclerotic conversion of many of the lesions,
with development of numerous pathologic stress fractures
that have failed to heal, despite operative intervention.
Keywords Cystic angiomatosis . Skeletal . Osteosclerosis .
Bisphosphonate therapy . Stress fracture
Introduction
Cystic angiomatosis (CA) is a multifocal hamartomatous
disorder of bone and viscera in which lesions are composed
of hemangiomatous or lymphangiomatous deposits or both
[1–5]. As in the patient described here, isolated skeletal
G. M. Shivaram : R. K. Pai : K. B. Ireland : K. J. Stevens (*)
Department of Radiology,
Stanford University School of Medicine,
Room S-062A, Grant Building, 300 Pasteur Drive,
Stanford, CA 94305-5105, USA
e-mail: kate.stevens@stanford.edu
cystic angiomatosis affecting the axial and appendicular
skeleton can occur [6–8], but concomitant disease of the
viscera exists in 60–70% of patients [9–11], usually in the
spleen but sometimes also in the liver, kidney, chest, and
lymph nodes [4, 5, 12, 13].
Typically, presentation is no later than in the patient’s
third decade [1], and there may be a higher prevalence
among men [1, 7]. Clinical symptoms, when present, can be
manifested either from skeletal or visceral involvement.
Bone pain can occur in areas of cystic lesions with or
without underlying pathologic fracture [14], and involve-
ment of adjacent soft tissue structures may cause localized
pain and swelling [5, 13]. CA affecting the vertebral
column may lead to localized back pain or even neurologic
symptoms from cord or nerve root involvement [15].
Hepatosplenomegaly, ascites, dyspnea, and hemoptysis are
associated with visceral CA [8, 13, 16, 17], and severe
organ failure can result in death. The clinical course is
variable, with a more favorable prognosis for those patients
without visceral disease [13, 18, 19].
We describe a case of skeletal CA occurring in a 35-
year-old Caucasian woman, and document the temporal
progression of the disease over a 15-year period. Notable
features of this case are late onset of disease, isolated
skeletal involvement, and osteosclerotic progression of the
patient’s lesions in the setting of long-term bisphosphonate
therapy.
Case report
A 35-year-old woman presented to an outside medical
facility in February 1992 with left shoulder pain. Radio-
graphs demonstrated an expansile lucent lesion, with
lattice-like trabeculation in the metadiaphyseal region of
1200 Skeletal Radiol (2007) 36:1199–1204

the proximal humerus. There was subtle cortical irregular-

ity, both medially and laterally, with associated periosteal
reaction, suggesting that there might have been a recent
pathological fracture (Fig. 1a). The periosteal reaction,
medially, resembled a Codman’s triangle, which is usually
associated with more aggressive bone lesions. A bone scan
showed avid radioisotope uptake in the proximal humerus
(Fig. 2), with no other areas of focal uptake. Biopsy of the
lesion was performed in April 1992, which resulted in
profuse bleeding from the biopsy site, suggesting a highly
vascular lesion. Initial review of the patient’s left humeral
biopsy at an outside medical center suggested a hemangi-
oma. In August 1992, the lesion was stabilized with
injection of methyl methacrylate cement, placement of
bone graft, and Steinmann pin fixation. Histology from a
specimen taken at the time of surgery showed mild
cytologic atypia in the endothelial lining of the vascular
spaces. This, in association with the radiographic findings,
led to a provisional diagnosis of a low-grade hemangio-
endothelioma of the left proximal humerus. The patient
initially experienced good symptom relief following the
procedure. However, a follow-up radiograph of the left
humerus in November 1992 showed an increasingly
expansile lesion in the area of previous surgery. This was
seen to increase gradually in size over the following years
on frequent radiographic follow up (Fig. 1b).
In December 1996, the patient began to complain of
non-specific pain in her thoracic spine and increasing pain Fig. 2 Bone scan in March 1992 showing marked uptake of
radiopharmaceutical agent in the left proximal humeral lesion
in her left humerus. Routine blood test results were normal,
apart from an elevated alkaline phosphatase level of 230 U/
l (normal 20–125 U/l). An MRI scan of the thoracic spine at
an outside facility showed numerous lesions throughout the the patient had undergone a prior MRI scan of her lumbar
visualized spine, suggestive of osseous metastases. Notably, spine in 1986, which had shown no vertebral abnormality.
A subsequent bone scan showed multiple areas of radio-
tracer uptake in her axial and appendicular skeleton, also of
concern for metastatic disease (Fig. 3). A skeletal survey
showed widespread mixed lytic and sclerotic lesions in the
spine, ribs, skull, clavicle, scapula, sternum, pelvis, humer-
us, and femur (Figs. 1b, 4a, and 5a). The lesions were well
defined and predominantly appeared sclerotic, with areas of
central lucency. Some lesions appeared more cystic, with a
thin sclerotic rim. Radiographs of the left humerus
indicated that the original lesion had increased minimally
in size, and an arteriogram showed the tumor to be highly
vascular. Biopsies of the left humerus, right clavicle, and
left posterior iliac crest were performed, and the initial
pathologic diagnosis from an outside hospital was, again,
that of a grade I hemangio-endothelioma. However, all the
Fig. 1 Changes of the left humerus occurring over time. a Antero- pathology specimens were subsequently reviewed at our
posterior (AP) radiograph in March 1992 shows an expansile lytic institution in conjunction with the radiographic studies. The
lesion of the proximal humerus, with cortical irregularity and
periosteal reaction, suggesting that there might have been a recent
pathologic features of the left humerus, left posterior iliac
pathologic fracture. b AP radiograph in July 1997 shows an increasing crest, and right clavicle biopsies were all identical, showing
expansile lesion, with cement and metal pins in place thin-walled vascular spaces within the marrow spaces of
Skeletal Radiol (2007) 36:1199–1204 1201

as areas of increased T2 signal, and the areas of sclerosis

correspond to low T1 signal intensity (Fig. 7). The number
and size of sclerotic lesions were also seen to increase on
serial MRI scans.
The patient has also developed recurrent bursitis,
tendinitis and tendinosis within both the right shoulder
and pelvis, thought to result from abnormal bone at the
tendinous insertions. In 2005, she developed stress fractures
in both her right foot and left proximal femur. Both of these
failed to respond to conservative treatment and needed
operative intervention. An intramedullary rod was placed
within the femur in August 2006, but, again, the fracture
showed no evidence of healing. The femur was subse-
quently plated in December 2006, with placement of bone
graft and a bone stimulator device, and is currently showing

Fig. 3 Bone scintigram in 1997 shows increased uptake in the

proximal humerus on the left. However, there are now multiple foci of
increased uptake in the right humerus, right clavicle, skull, spine,
pelvis and proximal femora

cancellous bone with associated reactive woven trabecular

bone (Fig. 6). These vascular spaces were dilated, filled
with blood, and lined by cytologically bland endothelial
cells without significant nuclear enlargement, pleomor-
phism, or mitotic activity to suggest a malignant vascular
neoplasm or hemangio-endothelioma. The findings were felt
to be, instead, characteristic of cystic angiomatosis of bone.
In March 1997 the patient underwent several cycles of
radiation to her thoracic spine and right hip and initially
experienced significant symptom relief. She was then
started on interferon and bisphosphonate therapy, with the
intent of stabilizing existing lesions and preventing the
formation of new angiomatous foci of bone lysis. Since
then, the bone lesions have been followed closely with both Fig. 4 Osseous changes of cystic angiomatosis occurring in the pelvis
radiographic skeletal surveys and MRI scans. Radiograph- over time. a Pelvic radiograph in 1997, demonstrating numerous
ically, the lesions have become more numerous and have rounded foci of bone sclerosis within the spine, pelvis and proximal
femora, some of which appear to have lucency centrally. b Pelvic
increased in size over time, with many of the more cystic radiograph in 2005, showing interval increase in the number of bone
appearing lesions becoming more sclerotic (Figs. 4b and lesions since the prior X-rays, many of which appear lucent, with a
5b). On MR images, the more lytic lesions were manifested sclerotic margin
1202 Skeletal Radiol (2007) 36:1199–1204

Fig. 5 Bony changes of the

right humerus occurring over
time. a Radiograph taken in
1998, showing small sclerotic
lesions in the metadiaphyseal
region of the proximal humerus,
some of which display lucent
centers. b Radiograph in 2007,
showing an increase in size of
the bone lesions in the right
humerus and on-going bony
sclerosis

evidence of callus formation. The stress fracture of the foot
has also failed to heal in the interim and will require further
intervention.
Discussion
In our patient, the first diagnosis of a cystic angiomatous
lesion was made when she was aged 35 years. The lesion of
her left humerus was presumed at that time to be a solitary
hemangioma, as the accompanying bone scan showed avid
uptake only in the left humerus. As new skeletal symptoms
developed over subsequent years, and further imaging
Fig. 6 Biopsy specimen from the left posterior iliac crest in 1997,
showing vascular spaces lined by a single layer of cytologically bland
endothelial cells associated with reactive trabecular bone. No features
of malignancy, such as nuclear pleomorphism or increased mitotic
activity, are identified. H & E, ×100
studies of her axial and appendicular skeleton were
obtained, lesions in various stages of progression were
discovered, including multiple sclerotic foci mimicking
metastatic disease. Currently, her disease appears to have
been stabilized, with no new osteolytic foci, although she
continues to experience debilitating pain from thoracic
spine involvement and has also developed several lower
extremity stress fractures in areas of osteosclerotic change.
This transformation of lytic bony areas into sclerotic ones
may reflect the natural progression of skeletal cystic
angiomatosis [6–8, 20]. However, the patient has also been
maintained on bisphosphonate therapy for 10 years, and
this medical treatment of her bone lysis may also have
contributed to the development of osteosclerosis within the
lesions [21, 22]. The patient’s recent history of poorly
healing lower extremity stress fractures occurring in the
region of sclerotic bone lesions may also be explained by
long-term bisphosphonate treatment. Recent clinical and
experimental data suggest that long-term administration of
bisphosphonates may lead to increased skeletal fragility and
development of spontaneous stress fractures secondary to
severe suppression of bone turnover [23–26].
Despite this long course of active and progressive
skeletal CA, at no time has the patient developed clinical
symptoms or imaging findings to suggest visceral involve-
ment. Biopsies taken from humerus, clavicle, and iliac crest
in lytic areas showed identical vascular lesions, composed
of dilated angiolymphatic spaces lined by endothelial cells
without the atypia characteristic of malignancy. The
pathologic differential diagnostic considerations in this case
include low-grade malignant vascular neoplasms such as
hemangio-endothelioma and angiosarcoma. Distinguishing
between benign and low-grade malignant vascular neo-
Skeletal Radiol (2007) 36:1199–1204
Fig. 7 a Coronal T1- and b)
coronal T2-weighted images,
with fat saturation, of the pelvis
in 2004, showing multiple
lesions with sclerotic margins in
the pelvis and proximal femurs
plasms involving bone can, at times, be difficult, especially
in cases such as this one with an unusual radiographic
appearance and involvement of multiple sites [27]. In our
patient, there was initial disagreement over the pathologic
diagnosis, with grade I hemangio-endothelioma, a low-
grade malignant vascular neoplasm with the potential for
metastasis, offered as an alternate possibility [28]. Initial
review of the patient’s left humerus, right clavicle, and left
posterior iliac crest biopsies at an outside medical center
noted mild cytologic atypia in the endothelial lining of the
vascular spaces, warranting classification as a hemangio-
endothelioma. However, further pathologic evaluation of
these specimens at our center and two other centers disagreed
with this opinion. The diagnosis of hemangio-endothelioma
requires the identification of plump, polygonal endothelial
cells with nuclear enlargement and hyperchromasia that are
typically set within a chondromyxoid matrix, features not
seen in this case. A diagnosis of low-grade angiosarcoma
was also entertained. However, the lesions seen in our patient
lack the characteristic, closely packed, interanastomosing
vascular channels lined by endothelial cells with enlarged
and hyperchromatic nuclei required for the diagnosis of
angiosarcoma [27]. The initial diagnosis of pathologic
malignancy may have been influenced by the multifocal
radiologic appearance of the patient’s skeletal lesions,
giving an appearance similar to widespread osteoblastic
metastases [6].
In summary, a 35-year-old woman presented initially
with a large angiomatous tumor of the left humerus,
progressing to widespread bony lesions subsequently
diagnosed as cystic angiomatosis of the skeleton. This case
is notable for the relatively late age of presentation, isolated
skeletal involvement, and progression of disease over a 15-
year period. The initial lesions were predominantly lytic,
but have gradually become osteosclerotic as the disease has
progressed, which may be secondary either to the natural
1203
history of the disease or long-term medical therapy with
bisphosphonates. Careful consideration of pathologic diag-
nosis is imperative in instances of widespread skeletal CA,
because the radiologic appearance may closely resemble
metastatic malignancy.
Acknowledgments We would like to thank Annette Wijsman for her
help in the preparation of this paper.
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