Case 4 -
David A. Owen, University of British Columbia, Vancouver, BC, Canada
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The patient is a 44 year old woman who presented with several masses in the liver. Clinically, they were assumed to represent metastatic carcinoma, but a needle biopsy did not confirm the diagnosis. The patient remained well for the next 10 years with no active medical treatment. At this time the masses were slowly enlarging and because of vague upper abdominal pain a surgical resection was performed. A representative section of these masses is provided.
Pertinent Laboratory Data:
At surgery, three liver masses were encountered with the largest measuring 10.0 X 6.0 X 6.0cm. The masses were poorly circumscribed and were rubbery in consistency. The largest mass extended to the inner margin of the liver capsule but not on to the serosal surface.
Case 4 - Slide 1
Hepatic hemangioendothelioma is a rare primary neoplasm. A majority of cases have no known clinical
cause. In a small minority of cases there is an association with exposure to vinyl chloride, hepatitis
B, hepatitis C and oral contraceptives. However, it is not clear whether this association is
coincidental or causative.
Approximately two thirds of neoplasms occur in women. The average age at presentation is in the
fifth decade (range 12 to 86 years) and only 5% of cases involve individuals <20 years old. Most
vascular tumors that occur in infants and children are examples of infantile hemangioma (formerly called
infantile hemangioendothelioma) which despite the similarity in name is a completely different entity.
The most common presentation is with abdominal pain but patients may also complain of nausea and
vomiting. Examination reveals hepatosplemomegaly with occasional jaundice and ascites. In 10% of cases
the neoplasm is discovered incidentally.
Because the tumors are multifocal within the liver, surgical resection of individual masses may not
be possible. Hepatic transplantation is now considered appropriate if the disease is advancing and
simple surgical excision is impractical.
Conventional imaging studies demonstrate multiple hepatic masses that may or may not have central
calcification. MRI imaging shows nodules with a multilayered targetoid appearance corresponding to
peripheral thrombosed vascular channels.
Morphologic and Immunophenoptypic Features
Epithelioid hemangioendotheliomas are typically multifocal and the nodules may vary considerably in
size. They are circumscribed but not encapsulated. When they are found in a subcapsular location the
nodules are commonly umbilicated. Slicing into the tumor masses reveals a uniform whitish or pale cream
appearance with a rubbery texture.
The histologic features of this tumor are characteristic. The center of the tumor is sparsely
cellular with abundant hyalinised fibrous tissue that often has a bluish appearance resembling cartilage
because of the production of mucopolysaccharides. As the lesion progress this cartilage-like tissue
becomes progressively eosinophilic and fibrotic. Eventually calcification may occur. Within this
central area small groups and individual tumor cells may be found. Three types of cell are encountered:
vacuolated cells, dendritic cells and intermediate cells. Typically, vacuolated cells have a
recognizable lumen. This lumen pushes the nucleus to one side resulting in a "signet ring" formation.
If larger lumina are present they may contain red blood cells. The dendritic cells have a spindle cell
or stellate morphology. Intermediate cells have mixed features. At the edges of the tumor nodules there
is considerably more cellularity and tumor cells infiltrate the liver parenchyma along sinusoids. At
this location the tumor has a more obvious vascular nature with endothelial cells having abundant pale
eosinophilic cytoplasm (epithelioid differentiation).
Tumor cells are invariably stain negative for mucin but commonly demonstrate immunohistochemical
features of epithelial differentiation (CK7 is positive in 50% of tumors, AE1/AE3 is positive in 35% and
pan keratin is positive in 12%). Other unusual positive immunohistochemical markers include smooth
muscle actin (positive in 30% of cases), and CD117 (positive in 15% of cases).
The key to the diagnosis is to recognize the vascular nature of the neoplasm and confirm it with
appropriate immunostains such as Factor XIIIA (positive in virtually 100% of cases), CD31 (positive in
90% of cases) and CD34 (positive in 80% of cases).
The case demonstrated is a woman aged 43 years at the time of her clinical presentation with masses
in the liver. Metastatic tumor was suspected but a needle biopsy demonstrated epithelioid
hemangioendothelioma. No active treatment was recommended. Ten years later the tumors had enlarged and
were causing significant abdominal distress. Orthotopic hepatic translation was carried out. She
remained well for four years when she developed two masses in the left lung. These were excised
surgically and proved to represent metastatic hemangioendothelioma. She remains well and tumor free the
present time: seventeen years after first presentation and seven years after hepatic transplantation.
Epithelioid hemangioendotheliomas are very slow growing neoplasms. The five year survival is
estimated at 43-55%. Surgery offers the main hope for cure and chemotherapy or radiotherapy are
generally not effective.
Differential Diagnosis :
Diagnostic problems are unlikely to arise in cases where the neoplasm is adequately sampled.
However, needle biopsies taken from the center of the lesion may reveal only small gland-like structures
set in a dense fibrous background. Positive immunostaining for CK 7 may lead to an erroneous diagnosis
of cholangiocarcinoma or metastatic upper GI adenocarcinoma. Epithelioid hemangioendotheliomas are
invariably negative with mucin stains such as PASD and mucicarmine indicating that these simple special
stains are still diagnostically valuable!! However, beware of the presence of entrapped non-neoplastic
bile ductules in any fibrosing hepatic neoplasm. As may be seen in the present case, surviving
non-neoplastic ductules may be found in the center of epithelioid hemangioendotheliomas. CD31 and CD 34
stains are positive in the cells lining the gland-like spaces. However, as the present case demonstrates
positivity may be scattered and weak. The dendritic cells are positive for Factor XIII and X111A and
usually these immunostains are useful and reliable. Intermediate cells may be negative for all
- Angioma with thrombosis and re-organization
- Metastatic adenocarcinoma (stomach or pancreas)
- Infantile hemangioma (hemangioendothelioma)
- Amyloid tumor
Infantile hemangioma is usually not a difficult diagnosis as most cases are diagnosed in the first
two years of life. Generally patients do not present with liver disease but do suffer from the effects
of arterio-venous blood shunting: typically cardiac failure and consumptive coagulopathy with
thrombocytopenia (Kassabach-Merritt syndrome). The most common histologic finding is an obviously
vascular neoplasm composed of intercommunicating channels lined by a single layer of bland endothelium
and separated by fine fibrous bands. Dilated cyst-like vessels represent tumor involution. Infantile
hemangiomas express GLUT1 and this immunostain can be used to differentiate them from congenital vascular
malformations. Infantile hemangiomas do not metastasize although they may be multifocal (spleen, lungs
and bone). If the infant survives any hemodynamic complications, the tumors tend to regress and rarely
require surgical resection.
Hemangiomas of the liver are common. Most of them occur in adults and are cavernous in type. They
usually present no diagnostic difficulty for pathologists although radiologic distinction from other
solid hepatocellular tumors may be difficult. Diagnostic problems can arise if an angioma undergoes
thrombosis with re-organization. This can be a particular problem with small biopsies where
distinguishing granulation tissue from a well differentiated angiosarcoma may not be straightforward.
Reliance has to be placed on finding pleomorphism and atypical mitoses in a sarcoma.
Angiosarcoma can be a difficult diagnosis to exclude. Generally poorly differentiated angiosarcomas
appear as obvious malignant neoplasms. They do not express epithelial markers and the diagnostic
challenge is to differentiate them from other types of sarcoma. Well differentiated angiosarcomas spread
by growth along the sinusoids. Generally they have recognizable nuclear pleomorphism and mitotic
activity. There is little tendency for angiosarcomas to develop central areas of hyaline connective
Amyloid deposition in the liver is generally diffuse and present in the space of Disse.
Occasionally, however, it may be found in a globular form (amyloid tumor) that can mimic the
cartilage-like fibrosis encountered in epithelioid hemangioendothelioma. Plump vessels may be seen in
the center of nodular amyloid and these could be confused with a sclerosing vascular neoplasm.
Epithelioid hemangioendothelioma with characteristic morphologic, immunohistochemical and clinical
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