Pediatr BIOOC! Cancer 2010;9999:1-3
Potential Response to Curcumin in Infantile Hemangioendothelioma of the Liver?
lewis A. Hassell MO,l *and le Dinh Roanh, MO, Ph02
A case of life-threatening infantile hemangioendothelioma of the
liver in a 6-month-old infant treated successfully with the dietary sup
plement curcumin is reported, with 6-year follow-up. Implications for
pathogenesis based on sites of action of curcumin are considered.
Pediatr Blood Cancer. 2010;9999:1-3. 02010Wiley-Liss, Inc.
Key words: angiogenesis factors; curcumin; infantile hemangioendothelioma of liver
Curcumin, derived from the spice turmeric (Curcuma tonga),
has a lengthy history in Oriental traditional medicine and has
anti-neoplastic activity in several animal models. In vitro, cur
cumin inhibits several signal transduction pathways, including those
involving protein kinase C, the transcription factor NF-KB, phos
pholipase A2 bioactivity, arachidonic acid metabolism, antioxidant
activity, and epidermal growth factor (EGF) receptor autophos
phorylation [11. It appears to directly inhibit angiogenesis in vivo,
perhaps through action on basic fibroblastic growth factor (bFGF)
rather than vascular endothelial growth factor (VEGF) . Cur
cumin also has an inhibitory effect on two groups of proteinases
involved in angiogenesis: members of the matrix metalloproteinase
family and the urokinase plasminogen activator family. Cell adhe
sion molecules are upregulated in active angiogenesis and curcumin
can block this effect, adding further to curcumin's anti-angiogenic
effect. Curcumin shows dose-dependent inhibition on tumor necro
sis factor, which affects angiogenesis through signal transduction
pathways, expression of proangiogenic factors, and cell adhe
sion molecules. Cell adhesion molecules are upregulated in active
angiogenesis and curcumin can block this effect, adding further
dimensions to curcumin's anti-angiogenic effect. Clinical trials are
underway using this agent against tumors of the colon [3.41, prostate
[51, pancreas [61, and others, while some clinical pilot studies have
shown potential tumor regression in tumors of the bladder, soft
palate, stomach, cervix, and skin .
Infantile hemangioendothelioma (lHE) is a relatively uncom
mon mesenchymal tumor of the liver. Some cases appear to
resolve spontaneously without treatment. Still 30% are pro
gressive and may result in death [8,91 from congestive heart
failure or coagulopathy-related bleeding despite intensive treatment.
Corticosteroids, chemoembolization, radiation therapy, and trans
plantation have been attempted in some ofthese cases . Recently,
treatment of infantile hemangiomas at various sites with propranolol
has shown promise [11,12]. IHE presents with liver enlargement
(distention), vascular shunting (cardiac failure), and other secondary
tumor effects, including hypothyroidism. Radiographic diagnosis is
possible, even antenatally. Since the outcome can be widely vari
able, effective treatment options without significant morbidities are
needed. Classification based on clinical, radiographic, physiologic,
and other features has been proposed together with a management
algorithm and registry for these cases to facilitate understanding and
treatment . We present a case of a serious, life-threatening IHE
successfully treated with the herbal extract curcumin.
© 2010 Wiley·Liss, Inc.?
Published online in Wiley InterScience?
A 6-month-old infant presented with lethargy and abdominal
swelling. Findings included an enlarged liver, rapid heart rate, and
symptoms of failure to thrive. Cardiac enlargement with a rounded
appearance and evidence of pleural effusion were present on chest
radiograph. Liver ultrasound revealed massive hepatic enlargement
with numerous hypoechoic lesions up to 15 cm. CT scan showed
lesions within liver segments II-VII (Fig. I). A surgical biopsy was
performed (Fig. 2). The patient had no cutaneous vascular lesions.
Thyroid function testing was not done.
Histology revealed a circumscribed, vascular neoplasm com
posed of small caliber vessels with bland endothelial lining cells.
A diagnosis ofIHE was rendered. Glut-I staining performed retro
spectively was positive.
Curcumin (400 mg/day, orally) was begun and continued for 9
months. Within 3 months improvement was evident. He had gained
weight and his activity and energy were age appropriate. By 6
months the liver was considerably smaller on exam. Repeat ultra
sound at I year showed no residual lesions in the liver. At 6 years,
the patient is thriving with no evidence of disease.
Treatment of IHE with curcumin is not a standard or novel advo
cated therapy for this disorder. Available options were limited to
steroids, supportive care, and radiation therapy. Given the limita
tions of the medical system where the patient resided, and since
the diagnosis was not made pre-operatively, the patient's successful
outcome without any of the co-morbidities associated with those
treatments is significant. In a tumor that often involutes sponta
neously, such an outcome may be ascribed to the natural history of
the disease rather than the effectiveness of the treatment. The series
reported by Kassarjian et a!. [141, which reflects a disease sever
ity cohort similar to this patient, only saw spontaneous regression
IUniversity of Oklahoma Health Sciences Center, Oklahoma City,?
Oklahoma; 2Center for Research and Early Detection of Cancer, Hanoi,?
Conflict of interest: Nothing to declare.?
*Correspondence to: Lewis A. Hassell, BMSB 451, 940 Stanton L.
Young Blvd, Oklahoma City, OK 73 J04.
Received 15 December 2009; Accepted 19 February 20 I0
2 Hassell and Roanh
Fig. 1. Ultrasound (A) and computed tomographic (B) appearance of
tumor masses (arrows, panel A; horizontal lines AB and CD, panel B) in
the liver at presentation and with resolution on ultrasound examination
(C) I year following treatment with curcumin (GAN P-right lobe of
liver; GAN TRAI-Ieft lobe of liver.).
in 24%, while the remainder were treated with steroids, interferon,
embolization, surgery, or a combination ofthose. All oftheir patients
with severity comparable to ours were treated without awaiting res
olution. Our patient's tumor was subsequently found to be positive
for Glut-I, a marker associated with higher proliferation rates and
mortality risk in IHE [15,16]. Thus, the successful outcome of treat
ment with an agent with known anti-angiogenesis properties within
a shorter timeframe than usually seen with spontaneous involution,
in our opinion, is more likely the result of true therapeutic effect.
These results offer potential insight into the pathogenesis of this
tumor. Since curcumin's molecular activity centers around the tran
scription factor NF-KB , this vascular proliferative pathway may
be operative in IHE. Additional impacts on anti-apoptosis (bcl-2
and others), proliferation (cyclooxygenase-2, cyclinD I, c-myc), and
Pediatr Blood Cancer DOl 10.1 002/pbc
Fig. 2. Gross appearance of tumor and representative histologic
appearance of infantile hemangioendothelioma showing vascular chan
nels (arrows) lined by cells with bland nuclear features (inset, 200x).
angiogenesis (VEGF and interleukin-8) products suggest that some
or all of these may also playa role in IHE . Triggers for this pro
liferation may act antenatally, since IHE has been detected in utero,
and within the first few weeks of life. Treatment of antenatal IHE
would be possible with curcumin, since it should cross the placenta.
Medicinal doses of curcumin are generally well tolerated,
although prolonged high doses do pose risk of liver toxicity .
Curcumin has a reported effect on the tumor suppressor p53 which
may be carcinogenic, so long-term impacts of treatment should be
In summary, we present a case of IHE treated with curcumin
with excellent outcome. While recognizing the confounding natu
ral history issues surrounding IHE, we believe further use of this
medication, in light of its safety profile and theorized mechanism of
action, is warranted in this neoplasm, and potentially in other infan
tile angiomatous tumors at other sites that have a similar natural
history. This response also suggests additional avenues of investi
gation into the pathogenesis of IHE.
The authors express appreciation to Karen Solodon for able sec
retarial and editorial assistance, to James Collins, Elizabeth Hassell,
and Kar-Ming Fung, MD, for photographic formatting help, and to
Dr. Do Hoang Duong, Dr. Tran cong Hoan, and Dr. Nguyen Thang
for providing the radiographic images.
[accessed November 30, 2009].?
2.? Arbiser JL, Klauber N, Rohan R, et al. Curcumin is an in vivo
inhibitor of angiogenesis. Mol Med 1998;4:376-383.
3.? National Institutes of Health. Use of curcumin for treatment of
intestinal adenomas in familial adenomatous polyposis (FAP).
22& rank=2 [accessed November 30, 2009].
4.? National Institutes of Health. Curcumin with pre-operative
capecitabine and radiation therapy followed by surgery for rec
tal cancer. clinicaltrials.gov/ct2/show?intr=%22Curcumin%22&
rank=7 [accessed November 30, 2009].
5.? National Institutes of Health. Trial of curcumin in cutaneous
t-cell lymphoma patients. clinicaltrials.gov/ct2/show?intr=%22
Curcumin%22& rank=IO [accessed November 30,2009].
6.? National Institutes ofHealth. Trial ofcurcumin in advanced pancre
atic cancer. c1inicaltrials.gov/ct2/show/NCT00094445 [accessed
November 30, 2009].
7.? Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of
oral curcumin: Biomarkers of systemic activity and compliance.
Clin Cancer Res 2004; 10:6847.
8.? Chen CC, Kong MS, Yang CP, et al. Hepatic hemangioendothe
lioma in children: Analysis of thirteen cases. Acta Paediatr Taiwan
9.? Presedo A, MartInez-Ibanez V, Castellote A, et al. Infantile hepatic
hemangioendothelioma of the liver: Report of 11 cases. Cir Pediatr
1996;9:51-54 [article in Spanish].
10.? DaHer JA, Bueno J, Gutierrez I, et aJ. Hepatic hemangioendothe
lioma: Clinical experience and management strategy. I PediatrSurg
1999;34:98-105, discussion 105-106.
II.? Buckmiller LM. Propranolol treatment for infantile hemangiomas.
Curr Opin Otolaryngol Head Neck Surg 2009; 17:458-459.
12.? Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al.
Propranolol for severe hemangiomas of infancy. N Engl J Med
13.? Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic
hemangiomas: Subtype classification and development of a clin-
Curcumin Treatment of Hemangioendothelioma
leal? practice algorithm and registry. I Ped Surg 2007;42:62
14.? Kassarjian A, Zurakowski D, Dubois J, et al. Infantile hepatic
hemangiomas: Clinical and ilnaging findings and their correlation
with therapy. AIR Am I Roentgenol 2004; 182:785-795.
15.? Mo JQ, Dimashkieh HH, Bove KE. GLUTl endothelial reactivity
distinguishes hepatic infantile hemangioma from congenital hepatic
vascular malformation with associated capillary proliferation. Hum
16.? Hernandez F, Navarro M, Encinas JL, et al. The role of GLUT1
immunostaining in the diagnosis and classification of liver vascular
tumors in children. J Pediatr Surg 2005;40:801-804.
17. Singh S, Aggarwal BB. Activation of transcription factor NF-KB
is suppressed by curcumin (diferuloyhnethane) [corrected]. I BioI
18.? Aggarwal S, Ichikawa H, Takada Y, et al. Curcumin (diferu
loylmethane) down-regulates expression of cell proliferation and
antiapoptotic and metastatic gene products through suppression
of IKBa kinase and Akt activation. Mol Pharmacol 2006;69: 195
19.? "Curcumin and Turmeric," Advanced Health Life Extension, Clear
Springs Press. www.advance-health.comlcurcumin.html.
20.? Moos PJ, Edes K, Mullally JE, et al. CurcUlnin impairs tumor
suppressor p53 function in colon cancer cells.. Carcinogenesis
Pediatr Blood Cancer DOl 10.1 002/pbc
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