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Infantile hemangioendothelioma with elevated serum α fetoprotein: report of 2 cases with immunohistochemical analysis

Department of Hospital Pathology, College of Medicine, the Catholic University of Korea, 150-713 Seoul, Korea.
Human pathology (Impact Factor: 2.77). 02/2010; 41(5):763-7. DOI: 10.1016/j.humpath.2009.05.019
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ABSTRACT

Infantile hemangioendothelioma is the most common benign mesenchymal tumor of the liver presenting during the first 6 months of life. Serum alpha fetoprotein is an important tumor marker for hepatoblastoma, hepatocellular carcinoma, and germ cell tumors. However, it is rarely elevated in patients with hepatic infantile hemangioendothelioma. In such cases, surgery may be done to rule out malignancies when alpha fetoprotein levels are high. The etiology of the elevated alpha fetoprotein level has not yet been elucidated. We report 2 cases of solitary hepatic infantile hemangioendothelioma and demonstrate immunohistochemically that hepatocytes near or entrapped within the tumor were the source of the increased serum levels of alpha fetoprotein explaining the unusual clinical presentation.

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Available from: Tae-Jung Kim, Sep 11, 2015
Case study
Infantile hemangioendothelioma with elevated serum
α
fetoprotein: report of 2 cases with
immunohistochemical analysis
Tae-Jung Kim MD, PhD
a
, Youn Soo Lee MD, PhD
a,
, Young Soo Song MD
b
,
Chan Kum Park MD, PhD
b
, Sang In Shim MD, PhD
a
,
Chang Suk Kang MD, PhD
a
, Kyo-Young Lee MD, PhD
a
a
Department of Hospital Pathology, College of Medicine, the Catholic University of Korea, 150-713 Seoul, Korea
b
Department of Pathology, College of Medicine, Hanyang University, 133-792 Seoul, Korea
Received 6 March 2009; revised 23 April 2009; accepted 13 May 2009
Keywords:
Infantile
hemangioendothelioma;
α fetoprotein;
Hepatoblastoma;
Liver
Summary Infantile hemangioendothelioma is the most common benign mesenchymal tumor of the liver
presenting during the first 6 months of life. Serum α fetoprotein is an important tumor marker for
hepatoblastoma, hepatocellular carcinoma, and germ cell tumors. However, it is rarely elevated in
patients with hepatic infantile hemangioendothelioma. In such cases, surgery may be done to rule out
malignancies when α fetoprotein levels are high. The etiology of the elevated α fetoprotein level has not
yet been elucidated. We report 2 cases of solitary hepatic infantile hemangioendothelioma and
demonstrate immunohistochemically that hepatocytes near or entrapped within the tumor were the
source of the increased serum levels of α fetoprotein explaining the unusual clinical presentation.
Crown Copyright © 2010 Published by Elsevier Inc. All rights reserved.
1. Introduction
Infantile hemangioendothelioma (IHE) is the most
common vascular tumor of the liver in infancy, accounting
for about 20% of all primary pediatric hepatic tumors. These
tumors are benign and can occur as solitary or multifocal
lesions [1,2]. The true incidence of this tumor is impossible
to determine, as many small lesions are asymptomatic and
remain undiagnosed. Of those that come to clinical attention,
90% are diagnosed during the first 6 months of life and 33%
are diagnosed during the first month [3]. Most lesions
continue to grow during the first year of life, then
spontaneously regress. Multiple lesions are difficult to treat
medically and carry a mortality rate as high as 70% [4].
Surgical resection is indicated if life-threatening symptoms
are present or if the mass cannot be distinguished from a
malignant tumor. Serum α fetoprotein (AFP), when adjusted
for the age of the infant, is rarely elevated in IHE. A few
patients with elevated serum AFP have been reported in the
literature [5-11]. In such cases, surgery may be performed to
rule out malignancy. We present 2 cases of surgically
resected IHE with elevated serum AFP and demonstrate
immunohistochemically that t he hepatocytes near or
entrapped within the tumor were the cause of this unusual
phenomenon. To our knowledge, this is the first report in the
English literature to immunohistochemically demonstrate the
possible cause for the elevated serum AFP in IHE.
Corresponding author.
E-mail address: lys9908@catholic.ac.kr (Y. S. Lee).
www.elsevier.com/locate/humpath
0046-8177/$ see front matter. Crown Copyright © 2010 Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.humpath.2009.05.019
Human Pathology (2010) 41, 763767
Page 1
2. Case report
2.1. Case 1
A 27-day-old female neonate was admitted with irritability.
Because of the suspicion of a urinary tract infection, the
patient underwent an abdominal ultrasound that revealed a
very large mass in the left lobe of the liver. Physical
examinatio n revealed hepatomegaly but wa s otherwise
unremarkable. Computed tomo graph y showed a 7.1 ×
6.5-cm exophytic mass in the lateral segment of the left
hepatic lobe (Fig. 1A). The central area of the mass was not
enhanced due to probable fibrosis or thrombosis. The serum
AFP level was 42 024 ng/mL (reference range for her age,
2654 ± 3080 ng/mL) [12]. Although the radiologic findings
were suspicious for IHE and hepatoblastoma could not be
ruled out because of the high AFP level, the patient underwent
surgical excision of the mass. Four days after surgery, the
AFP level was 38 501 ng/mL; the most recent serum AFP
level, measured 8 months after surgery, was 4.79 ng/mL
(reference range for her age, 8.5 ± 5.5 ng/mL) [12].
2.2. Case 2
A 4-month-old male infant with a history of neonatal
jaundice was suspected to have a hepatic cystic mass on
abdominal ultrasound. Computed tomography showed a
3.5 × 3.0 cm enhancing mass in the sixth segment of the right
hepatic lobe (Fig. 1B). Physical examination was unremark-
able. Complete blood count and coagulation studies were
normal, but the serum AFP level was as high as 325 ng/mL
(reference range for his age, 74 ± 56 ng/mL) [12]. The patient
underwent right segmentectomy of the liver to rule out
malignancy. The serum AFP level normalized, and complete
Fig. 1 Computed tomography of both cases revealed a mass with intense, peripheral nodular enhancement and irregular, central
nonenhancement (arrows; case 1 [A], case 2 [B]). The reddish brown tumor from case 1 appeared variegated on cut surface, with white areas of
central necrosis and scarring (C). The relatively well-demarcated mass from case 2 showed a dark brown cut surface with central scarring (D).
764 T. -J. Kim et al.
Page 2
blood count and blood chemistry were normal after surgery.
Despite a recommendation for regular follow-up visits, the
patient's parents did not seek care for the next 15 months. At
19 months, the patient presented with vomiting and died due
to suspected sudden-onset disseminated intravascular coag-
ulation. Autopsy revealed microthrombi in the kidneys and
liver but no evidence of recurrent IHE.
3. Pathologic findings
The surgical specimen from case 1 consisted of a
segmental resection of the liver that showed an ill-
demarcated reddish brown mass, 7.0 cm in diameter; it
appeared variegated with a central white area of necrosis and
scarring (Fig. 1C). The surgical specimen from case 2
consisted of a segmental resection of the liver showing a
relatively well-demarcated dark brown mass, 3.5 cm in
diameter, with a central area of scarring ( Fig. 1 D).
Microscopically, both lesions were composed of vascular
channels lined by a single continuous layer of plump
endothelial cells in a supporting fibrous stroma (Fig. 2A).
Foci of extramedullary hematopoiesis were noted within
vascular spaces at the periphery of the tumor and within
dilated sinusoids of the liver parenchyma adjacent to the
tumor (Fig. 2B). Mitoses were infrequent. A reas of
infarction, fibrosis, necrosis, and calcification occupied the
center of the lesion. Well-preserved proliferating bile ducts
were present in the supporting stroma, most frequently near
the periphery of the lesion.
Hepatocytes entrapped within the advancing edge, or near
the margin of the tumor, were round, with abundant, pale
cytoplasm and distinct cytoplasmic membranes. The
Fig. 2 Microscopic examination of both cases revealed irregular vascular channels composed of fibrous septa lined by endothelial cells (A,
hematoxylin and eosin, original magnification ×200). Extramedullary hematopoiesis was noted in the vascular spaces at the periphery of the
tumor and in the dilated hepatic sinusoids near the tumor edge. Inset, higher magnification showed erythroid and granulocyte precursors (B,
hematoxylin and eosin, original magnification ×200). Note the hepatocytes entrapped in the advancing edge and near the margin of the tumor
arranged in thick trabeculae, usually 2 to 3 cells thick (C, hematoxylin and eosin, original magnification ×400). Conversely, hepatocytes distal
to the tumor have a bland-looking morphology, and the trabeculae are one cell thick (D, hematoxylin and eosin, original magnification ×400).
765Infantile hemangioendothelioma with elevated serum
α
fetoprotein
Page 3
sinusoids were dilated. The cells were arranged in thick
trabeculae, usually 2 to 3 cells thick, with alternating light and
dark areas, reminiscent of fetal hepatocytes (Fig. 2C). Portal
tracts, bile ducts, and bile ductules were present in this area.
The hepatocytes distal from the tumor had a bland-looking
morphology, and the trabeculae were one cell thick (Fig. 2D).
Immunohistochemical studies were performed in both
cases; the plump endothelial cells lining the irregular
vascular channels were positive for CD34 (DAKO, Glostrup,
Denmark). The hepatocytes entrapped within the advancing
edge, or near the margin of the tumor, were positive for AFP
(DAKO, Glostrup, Denmark) in both cases. Many more
AFP-positive hepatocytes were seen in case 1 (Fig. 3A
and 3C left) than in case 2 (Fig. 3B and 3C right). However,
the hepatocytes distal to the lesion were negative for AFP in
both cases (Fig. 3D).
4. Discussion
The differential diagnosis of a pediatric hepatic mass
includes IHE, hepatoblastoma, mesenchymal hamartoma,
embryonal sarcoma, and cavernous hemangioma. Surgical
resection is the primary treatment of hepatoblastoma,
hepatocellular carcinoma, and mesenchymal hamartoma.
Combined surgery and chemoradiation is the treatment of
choice for embryonal sarcomas. However, conservative
medical therapy is the treatment of choice for IHE and
cavernous hemangiomas. Regarding patients with IHE,
management is not necessary in asymptomatic masses, but
steroids, embolization, or surgical resection may be
attempted in patients with mild congestive heart failure.
Arterial embolization and surgery are alternative methods of
management if steroids are ineffective. Laboratory studies
and ima ging studie s suc h as computed tomography,
magnetic resonance imaging, and ultrasonography must be
obtained to avoid life-threatening surgical complications.
Serum AFP is important for the evaluation of pediatric
hepatic masses; it serves as a tumor marker for hepatoblas-
toma, hepatocell ular carcinoma, and germ cell tumors.
α fetoprotein is the earliest serum albumin-like glycoprotein
to appear in the fetus. During early embryogenesis, it is
produced in the yolk sac; later, it is produced by hepatocytes
and gastrointestinal mucosa. The serum AFP decreases rapidly
after birth and reaches adult levels by 8 months of age.
Fig. 3 α fetoprotein is expressed only in the cytoplasm of hepatocytes near the margin of the tumor in both case 1 (A, * indicates tumor;
**, liver) and case 2 (B, * indicates tumor; **, liver). The AFP-positive hepatocytes showed cytoplasmic staining (C, left, case 1; right, case 2).
The hepatocytes distant from the tumor exhibited no AFP staining in either case (D, left, case 1; right, case 2).
766 T. -J. Kim et al.
Page 4
α fetoprotein is elevated at the time of diagnosis in up to 90%
of patients with hepatoblastoma, but levels are usually normal
in IHE. Therefore, a solitary hepatic mass and elevated serum
AFP level suggest the possibility of a hepatoblastoma.
Both cases in this study presented with unusually high
serum AFP levels when adjusted for age. The AFP level in
case 1 continued to be high 4 days after surgery because its
half-life in serum is 2 weeks in patients of such an age [12].
α fetoprotein normalized 33 days after surgery.
Morphologically normal hepatic cells are suspected of
contributing to the elevated serum AFP seen in the setting of
IHE; this occurs as a response to the tumor [10,11]. Our
immunohistochemical study revealed positive AFP staining
only in hepatocytes at the advancing edge or near the margin
of the tumor; however, hepatocytes distant from the tumor
had negative AFP staining. Furthermore, AFP-positive
hepatocytes were seen more frequently in case 1 than in
case 2, which correlated with the elevated AFP levels in both
cases: more than 8 times the normal AFP level in case 1 and
more than 3 times the normal AFP level in case 2. Previous
investigators have searched for the cause of the elevated AFP
levels in IHE by immunohistochemical studies. Chan et al
[13] and Seo et al [6] tried unsuccessfully to demonstrate
AFP expression in tumor cells. These findings suggest that
tumor cells are not responsible for the elevated AFP and
reinforces our results. Our study is the first immunohisto-
chemical study to demonstrate that hepatocytes near the
tumor may be responsible for the unusually elevated serum
AFP level seen in IHE.
In conclusion, infants with hepatic masses and elevated
serum AFP may have IHE. Using immunohistochemical
staining, we clearly documented that AFP is expressed by
hepatocytes near or trapped within the tumor and not by
tumor cells.
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767Infantile hemangioendothelioma with elevated serum
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fetoprotein
Page 5
  • Source
    • "Serum AFP concentrations decrease rapidly after birth and reach adult levels by 8 months of age. Increased serum AFP concentrations are rarely observed in patients with IHHE, with one study reporting that clinical symptoms, age at presentation, tumor size and AFP concentration were not significantly related to time required for complete tumor regression21-23). Similarly, only three of our patients had increased concentrations of AFP, with all three having multiple tumors; despite receiving different treatment modalities, all three showed nearly complete tumor resolution. "
    [Show abstract] [Hide abstract] ABSTRACT: Infantile hepatic hemangioendothelioma (IHHE) is the most common type of hepatic vascular tumor in infancy. We conducted this study to review our clinical experience of patients with IHHE and to suggest management strategies. We retrospectively analyzed the medical records of 23 IHHE patients (10 males, 13 females) treated at the Asan Medical Center between 1996 and 2009. Median age at diagnosis was 38 days (range, 1 to 381 days). Seven patients (30%) were diagnosed with IHHE based on sonographically detected fetal liver masses, 5 (22%) were diagnosed incidentally in the absence of symptoms, 5 (22%) had congestive heart failure, 3 (13%) had skin hemangiomas, 2 (9%) had abnormal liver function tests, and 1 (4%) had hepatomegaly. All diagnoses were based on imaging results, and were confirmed in three patients by histopathology analysis. Six patients were observed without receiving any treatment, whereas 12 received corticosteroids and/or interferon-alpha. One patient with congestive heart failure and a resectable unilobar tumor underwent surgical resection. Three patients with congestive heart failure and unresectable tumors were managed by hepatic artery embolization with/without medical treatment. At a median follow-up of 29 months (range, 1 to 156 months), 21 (91%) patients showed complete tumor disappearance or >50% decrease in tumor size. One patient died due to tumor-related causes. IHHE generally has a benign clinical course with low morbidity and mortality rates. Clinical course and treatment outcome did not differ significantly between medically treated and non-treated groups. Surgically unresectable patients with significant symptoms may be treated medically or with hepatic artery embolization.
    Full-text · Article · Jun 2011 · Korean Journal of Pediatrics
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    • "These phenomena could be helpful in monitoring the recurrence of the tumor. Imaging studies showed the presence of a space-occupying lesion in the liver and may provide a diagnosis or a differential diagnosis [17] . However, some cases undergoing involution may contain calcifications, fibrosis and vascular channel deficiencies which make it difficult to differentiate from other hepatic neoplasms. "
    Preview · Article · Jan 2010 · World Journal of Gastroenterology
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    Preview · Article · Jun 2010 · The Korean Journal of Hepatology
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