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Surgical Neurology 72 (2009) 728 – 732
www.surgicalneurology-online.com

Neoplasm

Multiple dynamic cavernous malformations in a girl:
long-term follow-up☆
Liang Chen, MD, PhD a , Yao Zhao, MD, PhD a , Zheng Chen, MD a , May Tee, MD b ,
Ying Mao, MD, PhD a,⁎, Liang-Fu Zhou, MD a
a

Department of Neurosurgery, Hua Shan Hospital, Fudan University, Shanghai Neurosurgical Center, Shanghai 200040, P.R. China
b
Department of Surgery, Vancouver General Hospital, University of British Columbia, Vancouver, Canada
Received 17 March 2009; accepted 5 April 2009

Abstract

Background: Cavernous malformations have generally been viewed as fairly benign vascular
lesions with low potential for causing massive hemorrhage.
Case Description: We present an interesting case of multiple CMs, several of which were formed de
novo and exhibited aggressive biological behavior resulting in recurrent episodes of intracranial
hemorrhage over a 10-year period. This case illustrates a dynamic and aggressive form of CMs.
Recent advances in our understanding of the molecular pathogenesis of CMs implicate genetics as an
important pathogenic factor, which is the most likely etiology of this patient's presentation.
Conclusion: Special challenges exist in managing young children with multiple, highly
aggressive CMs.
© 2009 Elsevier Inc. All rights reserved.

Keywords:

Cavernous malformation; Natural history; Hemorrhage; De novo formation; Vascular malformation

1. Introduction

2. Case Report

Cavernous malformations are low-flow, benign vascular
lesions that affect 0.4% to 0.8% of the population [10,11].
However, their potential for a more aggressive course has
also been recognized. We will describe this unique case of
multiple hemorrhages of CMs by outlining the patient's
initial presentation, radiologic findings, and histopathologic
findings over a 10-year follow-up period. We will conclude
with a discussion of recent advances in their potential for
serious complications.

2.1. History and operative interventions

Abbreviations: AVM, arteriovenous malformation; CECs, cavernous
malformation endothelial cells; CMs, cavernous malformations; CT,
computed tomography; DSA, digital subtraction angiography; MR,
magnetic resonance; VEGF, vascular endothelial growth factor; VM,
venous malformation.
☆
This study was supported by National Natural Science Foundation of
China grant 30371455 to Ying Mao.
⁎ Corresponding author. Tel.: +86 21 62489999x6042; fax: +86 21
62492884.
E-mail address: yingmao168@hotmail.com (Y. Mao).
0090-3019/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.surneu.2009.04.002

In May 1996, when this patient was a 6-month-old baby
girl, she was transferred to our hospital for evaluation of
inconsolable crying and vomiting. Emergency CT scan of
the head revealed 2 small hematomas in the left
parietooccipital lobe, which were thought to be CMs. The
patient recovered well after conservative therapy. Two
months later, the patient's symptoms recurred and a repeat
CT scan showed rebleeding of the same CMs. This was also
treated conservatively.
Two years later, this patient presented with a more severe,
third episode of intracranial hemorrhage that was associated
with somnolence and required admission to our neurosurgical intensive care unit. In addition to the enlarging hematoma
in the left parietooccipital lobe, CT scan also demonstrated a
separate, expanding hematoma in the left cerebellum as well
as a smaller hemorrhage originating from the right frontal
lobe. Despite significantly elevated intracranial pressure,
there was no imminent threat of herniation; hence, con-

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Fig. 1. CT (A-E, H) and MR (F, G) manifestations of 2 hemorrhagic CMs in the left parietooccipital lobe. Initial CT scan (A) revealed 2 small hematomas in the
left parietooccipital lobe, with the parietal one enlarging 2 months later (B). Rehemorrhage of this CM occurred 2 years later (C). At that time, continuous
enlargement of the occipital lesion was found (D, E). MR (F) was performed after absorption of the hematoma. Postoperative MR (G) and CT (H) showed
complete resection of the CMs.

servative therapy was once again followed. The patient
eventually recovered well except for mild gait ataxia.
Further investigations were pursued once the patient
was stabilized from her acute illness. Digital subtraction
angiography of the brain was unremarkable. Von HippelLindau disease was effectively ruled out by a normal
abdominal CT scan, as well as a normal dilated fundoscopic examination. A familial cause was also explored
but denied.
The left cerebellum CM was resected in March 2001. This
was followed by resection of the remaining 2 CMs in the
parietooccipital lobe in July 2002 under neuronavigation. In
January 2006, however, this patient underwent episode of
brain hemorrhage derived from a suspected CM in the left
frontal lobe that was not seen in previous CT or MR images.
After the hematoma was absorbed, a third operation was
recommended to the patient's family, although the patient's
family remains hesitant and will likely opt for continued
surveillance and follow-up.

The patient is currently 11 years old, developmentally
normal, and otherwise well except for mild gait ataxia. She
presents almost all forms of CM biological behavior,
including the de novo formation of the left frontal CM, the
concurrent overt hemorrhages of the CMs in the left parietaloccipital lobe and left cerebellum, and the dynamic changes
from de novo formation, maturation, to total calcification of
the right frontal CM. Serial CT and MR images of the 5
lesions over a 10-year period are presented in chronological
order (Figs. 1-4, Table 1).
2.2. Histopathologic findings
The pathologic specimens of the left parietooccipital and
left cerebellar vascular lesions revealed CMs with typical
histopathologic features. These specimens were composed
of dilated, thin-walled vascular channels consisting of
endothelium and collagen, filled with blood and thrombi,
without intervening neural parenchyma within the bulk of
lesion. We did not find any significant difference in

Fig. 2. The formation and signal change of a CM in the right frontal lobe on CT and MR images. Nothing abnormal was found in the right frontal lobe on initial
CT scan (A). Two years later, a lesion of slightly high density was found near the anterior horn of the lateral ventricle (B). The MR (C) confirmed this finding, but
this lesion did not demonstrate features consistent with a typical CM. After the absorption of the small hematoma, the lesion becomes unclear as to its identity on
CT scan (D), although T2-weighted MR images (E) show a lesion with a low-signal ring, which is typical of CM. The CT (F) shows several intralesional
hemorrhages. Obvious low-signal change is found both on T1- and T2-weighted MR images (G, H), which we believe is due to intralesional calcification, a
consequence of the lesion aging.

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Fig. 3. CT and MR manifestations of a CM in the left cerebellum. Initial CT scan (A) was normal, but a small lesion of high density was found in the left
cerebellum near the cerebellar vermis (B) 2 years after the patient's initial presentation. Two weeks later, overt hemorrhage was seen on CT and MR images
(C, D). The hematoma eventually self-absorbed (E), and the preoperative (F, G) and postoperative (H) MR images are shown.

pathologic features among the CMs of this patient and the
CMs of our other patients.
3. Discussion
Because the prevalence of the CMs reaches 0.3% to 0.4%
of the population, and only a few patients show clinical
symptoms, the biological behavior of CMs seems to be

relatively benign in most cases. However, there appears to be
a subset of patients with aggressive lesions that demonstrate
de novo formation, rapid growth, and high risk for
hemorrhage [3,4].
3.1. Intracranial hemorrhage and CMs
Cavernous malformations are 1 of 4 types of cerebral
vascular malformations, which include AVM, CM, VM, and

Fig. 4. Sudden hemorrhagic onset of a CM in the left frontal lobe. Previous CT (A, F) and MR (B-E) images did not reveal any abnormalities over the 8-year
period. At the most recent presentation in January 2006, extralesional hemorrhagic was found on CT scan (G).

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Table 1
Ten-year summary of this patient's clinical presentation of multiple, hemorrhagic CMs
Location of CM

Date of CM
discovery

Date of catastrophic
hemorrhage

Chief complaint
on presentation

Treatment and outcome

Radiologic findings

Left parietal-occipital, ×2

May 1996

See Fig. 1

Mar 1998

Headache, vomiting,
visual disturbance
N/A

Surgical resection, resolved

Right frontal

Mar and May 1996;
Mar and Apr 1998
N/A

See Fig. 2

Left cerebellum

Mar 1998

Mar 1998

See Fig. 3

Left frontal

Oct 2002

Jan 2006

Headache, vomiting,
gait ataxia
Headache, vomiting

Close follow-up and
surveillance, lesion calcified
Surgical resection, resolved
Surgical resection recommended

See Fig. 4

N/A, not applicable.

capillary telangiectasia. As CMs are low-flow, low-pressure
vascular lesions, hemorrhage of a CM is more likely to be
self-limited compared to an AVM. Intralesional hemorrhage
of a CM suggests the hemorrhage remains confined to its
capsule; this presents as mild discomfort and is often referred
to as occult intracranial bleeding. Overt hemorrhage is less
common than occult hemorrhage. A retrospective rate of
overt hemorrhage was thought to be 0.25% to 2.3% per
patient year and a prospective rate of 2.6% to 3.1% per
patient year [10,11]. The expansion of intralesional hemorrhage or the extralesional hemorrhage could hardly lead to
intracranial hypertension and eventually brain herniation.
The only lethal hemorrhage, so far as we know, was reported
by Ciurea et al [4], with the lesion in the vital brainstem.
Another interesting aspect of this case is this patient's
multiple CMs, which have simultaneously hemorrhaged. To
our knowledge, this uncommon phenomenon has only been
reported by Chanda et al [3] in 2002, with one lesion in the
occipital lobe and the other in the dorsal brainstem of his
patient. The close proximity and distribution of these lesions
is similar to that of our patient. We suspect that the CMs
bled after simultaneous stimulation by presumably a type of
hormone that could not be confirmed currently. Maiuri et al
[8] studied the expression of angiogenic factors and growth
factors in the walls of cavernoma vessels, perivascular
tissue, and perilesional brain parenchyma. Results show that
the familial occurrence and more aggressive clinical
behavior of CMs are associated with higher expression of
Ki-67 and bcl-2 in the cavernoma tissue, which is associated
with higher expression of some growth factors in the
perilesional brain parenchyma. These findings suggest
neighboring vasculature and glia may be predisposed to
and recruited for further growth and progression. In a
previous study, we developed a modified protocol to isolate
and culture cerebral CECs from surgically resected human
specimens [12]. This study provided evidence that CECs
had enhanced angiogenic potential and showed increased
responsiveness to VEGF.

genetics. Cavernous malformations with multiple foci have
also been studied and a genetic basis for this disorder has
been suggested. Three genes (CCM 1, 2, 3) have been
identified in cases of familial CMs and sporadic cases with
multiple CMs [1,2,5,7]. We have also reported on hereditary
CMs in a Chinese family characterized by a novel CCM1
gene mutation [9]. In this patient's case, although no one in
the family had a similar problem and MR of her parents was
otherwise normal, we suspect some genetic factor may
explain this patient's young age of onset, multiple sites
of CMs, aggressive nature of these CMs, and their de
novo formation.
3.3. Therapeutic considerations for multiple CMs
in children
Although there may be simultaneous bleeding in 2 or
more lesions, surgical treatment should be undertaken for
lesions jeopardizing critical structures or exerting mass
effects [3], especially for a young child [6]. In our patient, the
lesion in the left cerebellum was the most life-threatening
and was removed before the parietal-occipital ones.
In terms of timing for surgical intervention, emergency
hematoma removal is not recommended unless there are
suggestions of imminent brain herniation. When an
extralesional hemorrhage occurs, the compression effect
of the hematoma may prevent rebleeding of the CM by a
tamponade-like effect, which may render the bleeding selflimiting. Symptoms usually resolve by spontaneous
resorption of the hematoma. Surgery at that time will
significantly lower the injury to the surrounding normal
brain parenchyma, as the representative mulberry feature
of the CM makes it distinguishable under the microscope
and the low signal ring around the CM becomes more
evident on MR.
Finally, because of the potential for de novo formation
and rapid enlargement of existing lesions, children with CMs
need to be followed carefully and regularly even when
lesions have been quiescent for several years [6].

3.2. Dynamic changes of CMs
Cavernous malformations are generally regarded as
congenital lesions and their de novo formation is thought
to be unusual. When this occurs, it is often associated with
radiation exposure, traumatic injury, or may be attributed to

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