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CHAPTER 7
Vascular Tumours
Benign vascular tumours are very common and most frequently
occur in the skin (see WHO classification of skin tumours). At all
sites, it is often difficult to determine whether benign vascular
lesions are malformations, true neoplasms or, in some cases,
reactive processes. Similarly, it remains essentially impossible
to reliably distinguish blood vessel endothelium from lymphatic
endothelium, which probably reflects the close functional and
embryogenetic relationship between these cell types.
Changes and advances since the 1994 WHO classification
include the characterization of various newly recognized
entities, particularly in the categories of intermediate maligna-
ncy, including the kaposiform, retiform and composite types of
haemangioendothelioma. Use of the term  haemangioendothe-
lioma remains problematic since, in the past, this term has been
used variably for benign, intermediate and malignant lesions. In
current practice, the term usually connotes intermediate malig-
nancy, except in the context of epithelioid haemangioendothe-
lioma, the metastatic rate of which is high enough (albeit much
lower than conventional angiosarcoma) to justify its classifica-
tion as malignant.
Angiosarcomas in soft tissue are now more frequently recog-
nized, in large part to the realization that many such tumours
have epithelioid cytomorphology at deep soft tissue locations,
including the pleural and peritoneal cavities.
bb5_12.qxd 13.9.2006 10:58 Page 156
E. Calonje
Haemangiomas
Synovial haemangioma joint effusion {509}. Recurrent pain is a ICD-O code 9132/0
frequent symptom. In about one third of
Definition cases pain is not a feature. Magnetic res- Synonyms
Synovial haemangioma (SH) is a benign onance imaging is the best radiological Intramuscular haemangioma, intramus-
proliferation of blood vessels arising in a technique to identify the lesion particu- cular angiolipoma.
synovium-lined surface, including the larly with regards to the extent of involve-
intra-articular space and bursa. Similar ment {835}. Epidemiology
lesions occurring within the tendon Although relatively uncommon, IA is one
sheath do not fall into this diagnostic ca- Aetiology of the most frequent deep-seated soft
tegory. The presentation of most lesions at a tissue tumours. The age range is wide
young age suggests that SH is a form of but adolescents and young adults are
Epidemiology vascular malformation. Trauma is unlike- most commonly affected (in up to 90% of
SH is very rare. Most patients are chil- ly to be of relevance in the pathogenesis. cases) {44,152,651}. Lesions have often
dren or adolescents and there is a been present for many years and it is
predilection for males {509}. Macroscopy therefore likely that many examples are
Numerous congested, variably dilated congenital. There is an equal sex inci-
Sites of involvement vessels of different calibre can be seen dence.
The most common site by far is the knee, and the tumour can be fairly circum-
followed much less commonly by the scribed or diffuse. Sites of involvement
elbow and hand. IA most commonly affects the lower limb,
Histopathology particularly the thigh, followed by the
Clinical features The tumour often has the appearance of head and neck, upper limb and trunk.
The tumour presents as a slowly growing a cavernous haemangioma with multiple Rare cases can present in the medi-
lesion often associated with swelling and dilated thin-walled vascular channels. A astinum and retroperitoneum.
smaller percentage of cases have the
appearance of either a capillary or arte-
riovenous haemangioma. The vascular
channels are located underneath the
synovial membrane and are surrounded
by myxoid or fibrotic stroma.
Haemosiderin deposition can be promi-
nent. Secondary villous hyperplasia of
the synovium is present in some cases.
Prognostic factors
A
Small lesions are usually easy to remove
completely with no risk of local recur-
rence. When more diffuse involvement of
the joint is present, complete excision
can be difficult to achieve.
Intramuscular angioma
B
Fig. 7.02 Intramuscular haemangioma. A This lesion
Definition
was excised from the rectus abdominis muscle of a
Intramuscular angioma (IA) is defined as
young adult female. Note the poorly circumscribed
a proliferation of benign vascular chan-
margins and prominent fatty stroma. B Extensive
Fig. 7.01 Synovial haemangioma. A mixture of cav- nels within skeletal muscle and it is asso- replacement of the muscle by dilated vascular chan-
ernous and capillary vascular channels underlie ciated in most instances with variable nels with focal thrombosis. Note the prominent
the synovium.
adipocytic component.
amounts of mature adipose tissue.
156 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 157
A B C
Fig. 7.03 Intramuscular haemangioma. A Predominance of cavernous-like vascular spaces. B Extensive adipocytic component with muscle atrophy. C Entrapped
muscle fibres with hyperchromatic, reactive nuclei.
Clinical features tive nature of the tumour often results in ICD-O code 9122/0
The typical presentation is that of a slow- degenerative/reactive sarcolemmal
ly growing mass which is often painful, changes with hyperchromatic nuclei. Epidemiology
particularly after exercise. Pain is mainly Pure VHs are rare and mainly present in
present in tumours located in the limbs. Prognostic factors adults.
Radiological examination often reveals The rate of local recurrence is high
the presence of calcification secondary (between 30 to 50%) and therefore wide Sites of involvement
to phleboliths or metaplastic ossification. local excision is recommended. Tumours present in the subcutaneous or
deeper soft tissues with predilection for
Aetiology the limbs.
It is likely that these lesions are malforma-
tions and there is no relation to trauma. Venous haemangioma Clinical features
VH often presents as a long-standing
Macroscopy slowly growing tumour. Radiological
Tumours are often large and there is dif- Definition examination often shows the presence of
fuse infiltration of the involved muscle. Venous haemangioma (VH) is composed calcification due to phleboliths.
Variably sized vascular channels with of veins of variable size, often having
thrombosis and haemorrhage are usually thick muscular walls. Intramuscular Aetiology
readily seen. The appearance of the angiomas and angiomatosis can be The clinical evolution and clinicopatho-
tumour can be solid and yellowish as a composed almost exclusively of veins logical features suggest that these
result of the presence of adipose tissue. but are usually intermixed with other ves- lesions represent vascular malforma-
Lesions also appear solid when capillar- sel types. These subtypes are described tions.
ies predominate. under their respective headings.
Macroscopy
Histopathology VH is ill defined and consists of dilated
IA has been traditionally classified congested vascular spaces with areas of
according to the vessel size into small haemorrhage.
(capillary), large (cavernous) and mixed.
This is not practical, however, as most Histopathology
tumours contain a mixture of vascular VH typically consists of large thick-
channels frequently including lymphat- walled vessels, which are variably dilat-
ics. IA usually consists of large thick- ed and commonly display thrombosis
walled veins, a mixture of cavernous-like with occasional formation of phleboliths.
vascular spaces and capillaries or a Widely dilated vessels can show atte-
prominent arteriovenous component. nuation of their walls, mimicking a ca-
Tumours purely composed of capillaries vernous haemangioma.
have a predilection for the head and Elastic stains reveal the absence of an
neck area and those with a predominant internal elastic lamina. This aids in the
cavernous lymphatic component are distinction from an arteriovenous hae-
seen mainly on the trunk, proximal upper mangioma.
limb and head. Variable amounts of
mature adipose tissue are almost always Prognostic factors
present and may be very prominent. This Deep-seated tumours are difficult to
explains why IA was sometimes known in excise and can recur locally but subcu-
the past as angiolipoma {1264}. Atrophy taneous tumours do not show a tendency
Fig. 7.04 Venous haemangioma with typically
to recur.
of muscle fibres secondary to the infiltra- numerous prominent thick-walled veins.
Haemangiomas 157
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Arteriovenous haemangioma
Definition
Arteriovenous haemangioma (AVH) is a
non-neoplastic vascular lesion charac-
terized by the presence of arteriove-
nous shunts. There are two distinctive
variants {63,1825}: deep-seated and
cutaneous (cirsoid aneurysm or acral
arteriovenous tumour; see WHO classi-
fication of skin tumours).
When these lesions involve multiple tis-
sue planes, they are termed angiomato-
sis (see page 161). AVH should not be
confused with juvenile, cutaneous (cel-
lular) haemangiomas as they do not
regress spontaneously.
ICD-O code 9123/0
A
Synonym
Arteriovenous malformation.
Epidemiology
Deep-seated AVH is uncommon and
affects children and young adults.
Sites of involvement
AVH affects predominantly the head
and neck followed by the limbs.
Clinical features
B C
Angiography is an essential tool to con-
Fig. 7.05 Arteriovenous haemangioma. A In some cases, cavernous vascular spaces predominate.
firm the diagnosis and establish the
B Extensive infiltration of the subcutaneous tissue by large vessels. C An elastic stain is useful to determine
extent of the disease. Lesions are often
the type of vessels (elastic van Gieson).
associated with a variable degree of
arteriovenous shunting and this can be
severe enough to induce limb hypertro-
phy, heart failure, and consumption Histopathology diagnostic clue.
coagulopathy (Kasabach-Merritt syn- This diagnosis always requires clinico- Elastic stains are helpful in distingui-
drome). Pain is also a frequent symptom pathological and radiological correla- shing between arteries and veins.
and superficial cutaneous changes tion. AVH is characterized by large Negative GLUT-1 staining may facilitate
mimicking Kaposi sarcoma clinically numbers of vessels of different size, distinction from juvenile haemangioma
and histologically can be seen (pseudo- which include veins and arteries with {1582}.
Kaposi sarcoma or acroangiodermatitis) the former largely outnumbering the lat-
{2046}. The presence of shunting can ter. Areas resembling a cavernous or Prognostic factors
be confirmed clinically by auscultation. capillary haemangioma are frequent, as Treatment is difficult because of the
are thrombosis and calcification. degree of involvement, which has to be
Macroscopy Recognition of arteriovenous shunts is determined by angiographic examina-
Tumours are ill defined and contain vari- difficult and requires examination of tion. Local recurrence is common
able numbers of small and large blood numerous serial sections. Fibrointi- because of the difficulties in achieving
vessels, many of which are dilated. mal thickening in veins is a useful complete excision.
158 Vascular tumours
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J.F. Fetsch
Epithelioid haemangioma
Definition the subcutis, with dermal examples Macroscopy
A benign vascular tumour with well being less frequent, and deep-seated These lesions are usually 0.5 2.0 cm in
formed but often immature vessels, cases being rare {661, 1612}. Rare size, with rare examples exceeding 5
the majority of which are lined by cases arise from a large vessel. The cm {1612}. Apart from size, the gross
plump, epithelioid (histiocytoid) most frequent preoperative clinical characteristics of this process are not
endothelial cells with amphophilic impressions are an epidermal cyst or well-described. Many examples may
or eosinophilic cytoplasm and a angioma {1612}. have a rather nonspecific nodular
large nucleus with an open chromatin appearance. Some examples with
pattern and central nucleolus. Aetiology retained blood may have an appear-
Subcutaneous examples are usually There remains considerable controversy ance suggestive of a haemangioma.
associated with a muscular artery. Most as to whether epithelioid haeman- Occasionally, subcutaneous examples
cases have a prominent inflammatory gioma (angiolymphoid hyperplasia may resemble a lymph node because of
component. with eosinophilia) is a reactive lesion circumscription and a peripheral lym-
or a true neoplasm. Features that lend phoid reaction.
ICD-O code 9125/0 support for a reactive process include:
1) a predilection for superficial soft Histopathology
Synonyms
tissue sites that overlie bone and have Subcutaneous examples of epithelioid
Angiolymphoid hyperplasia with eosi- minimal soft tissue padding, coupled haemangioma are characterized by
nophilia {314, 661, 1059, 1384, 1612, with a compelling history of trauma a prominent proliferation of small,
1805, 2248}, nodular angioblastic in up to 10% of cases {661,1612}, capillary-sized vessels lined by
hyperplasia with eosinophilia and 2) a tendency for subcutaneous plump, epithelioid endothelial cells.
lymphofolliculosis {158}, subcutaneous examples to be well delineated and The vessels typically have an im-
angioblastic lymphoid hyperplasia with symmetrically organized around a mature appearance and they may lack
eosinophilia {1769} and inflammatory larger vessel that may have evi- a well defined lumen, but they are
angiomatoid nodule. dence of damage (e.g., fibro- well formed with single cell layering
intimal proliferation, a disrupted of the endothelium and an intact
Epidemiology elastic lamina, or mural disruption), myopericytic/smooth muscle layer.
Epithelioid haemangioma affects a wide 3) a pronounced inflammatory reac- The endothelial cells have amphophilic
age range, peaking in the third through tion, and 4) some morphologic evi- or eosinophilic cytoplasm that is
fifth decades {661, 1612}. Females dence supporting lesional maturation sometimes vacuolated, and they
appear to be affected more commonly over time. However, the alternative view contain a single, relatively large,
than males. that this is a true benign neoplasm nucleus with an open chromatin
with self-limiting biologic potential pattern, and often, a central nucleolus.
Sites of involvement cannot be dismissed, especially in The process is usually well demar-
The most frequently affected sites are view of the local recurrence rate. cated from the surrounding soft tissue,
the head, especially the forehead, and commonly, it is associated with
preauricular area, and scalp (often in (sometimes centred around) a larger
the distribution of the superficial vessel, usually a muscular artery.
temporal artery), and the distal portions An inflammatory milieu rich in
of the extremities, especially the digits eosinophils and lymphocytes is
{661,1612}. present in the overwhelming majority of
cases, and many examples are
Clinical features bordered by a prominent lymphoid
The majority of patients present with a reaction with follicle formation. It is
mass of a year or less in duration. common to encounter epithelioid
However, some examples have been endothelial cells within the lumen of
reported to be present for as many the larger vessel, either replacing
as 15 years before excision {661,1612}. part of the normal endothelial
The process is usually uninodular, lining or "coating" fibrin fronds, as
Fig. 7.06 Subcutaneous epithelioid haemangioma,
but multinodularity (generally in con- seen in papillary endothelial hyper-
showing circumscription, a peripheral lymphoid
tiguous areas) is encountered with plasia. Cross-sections of the larger
reaction, and symmetrical growth around a
some frequency. Most examples affect muscular artery. vessel may also reveal epithelioid
Epithelioid haemangioma 159
bb5_12.qxd 13.9.2006 10:58 Page 160
endothelial-lined channels that trans- the vessels often have a more mature Immunophenotype
gress the vessel wall and communicate appearance with a well canalized The epithelioid endothelial cells of epithe-
with the surrounding vascular prolifera- lumen, and the endothelial cells are lioid haemangioma are immunoreactive
tion. somewhat less plump, frequently more for CD31 and factor VIIIrAg. Immuno-
Dermal examples of epithelioid hae- cobblestone or hobnail-like in appear- reactivity for CD34 is also present, though
mangioma also feature a proliferation of ance. Also, dermal examples are less often to a lesser degree. Infrequently, lim-
small vessels, lined by epithelioid circumscribed and often lack lymphoid ited keratin expression may be detected.
endothelial cells, set in an inflammatory follicles. Finally, these superficial lesions Immunostaining for alpha-smooth muscle
milieu rich in lymphocytes and are not usually associated with a larger actin or musclespecific actin is helpful in
eosinophils. However, in this location, central vein or muscular artery. demonstrating an intact myopericytic
layer around the immature vessels. Actin-
positive myopericytes are generally pres-
ent to a much lesser extent in malignant
vascular tumours such as epithelioid
haemagioendothelioma and epithelioid
angiosarcoma.
Prognostic factors
Complete local excision and follow-up
are optimal management for epithelioid
haemangioma. Local recurrence is
reported to occur in up to one-third of
patients {1612}. Whether this is due to
persistence of an underlying vascular
anomaly (e.g., an arteriovenous shunt)
that incites regrowth or an indication of
true neoplastic potential is unresolved.
Metastases do not occur. There is one
report of apparent regional lymph node
seeding that had no adverse affect on
patient outcome with 5 years follow-up
{1769}.
A
B C
Fig. 7.08 Epithelioid haemangioma. The epithelioid
Fig. 7.07 Epithelioid haemangioma. A Involvement of a muscular artery. Note the presence of an intraluminal
component, and the immature, but well formed, vessels around the artery. B,C Immature vessels, lined by epithe- endothelial cells are strongly reactive for factor
VIIIrAg.
lioid endothelial cells. Note the presence of an inflammatory infiltrate rich in lymphocytes and eosinophils.
160 Vascular tumours
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S.W. Weiss
Angiomatosis
Definition Females are affected with slightly greater tered haphazardly throughout soft tis-
Angiomatosis is a diffuse form of haem- frequency than males {1758}. sue. The venous vessels contain irregu-
angioma that affects a large segment of larly attenuated walls from which clus-
the body in a contiguous fashion, either Sites of involvement ters of smaller vessels herniate in bou-
by vertical extension, to involve multiple Over one half of cases occur in the lower quet-like arrangement. In the second
tissue planes (e.g. skin, subcutis, mus- extremities, followed by the chest wall, pattern the lesion resembles an infiltrat-
cle, bone), or by crossing muscle com- abdomen, and upper extremity. ing capillary haemangioma. Large
partments to involve similar tissue types amounts of mature fat frequently accom-
(e.g. multiple muscles). This definition Clinical features pany both types. Although the first
implies that the diagnosis is a combined Patients present with diffuse persistent pattern is highly characteristic of
clinical and pathological one. swelling of the affected part, which occa- angiomatosis, the diagnosis should not
sionally waxes and wanes in size and is be made on this pattern alone, but on
Synonyms and historical annotation affected by strenuous activity. Only rarely the combination of these changes in
Vascular malformation, arteriovenous is significant arteriovenous shunting association with the clinical features
malformation, and venous malformation leading to gigantism observed. Plain {2240}.
have been employed as synonyms for films of the affected region show an ill Rare lesions with prominent glomus cells
angiomatosis. These earlier terms under- defined mass which on CT scan can are classified as glomangiomatosis (see
score the prevailing view that angiomato- sometimes be identified as vascular due page 136).
sis probably represents congenital mal- to the presence of serpinginous densities
formations (rather than neoplasms) corresponding to tortuous veins. Clinical behaviour
which make their appearance during Although angiomatosis is considered a
childhood. The term "infiltrating angi- Macroscopy / Histopathology benign lesion, nearly 90% of cases per-
olipoma"; used to refer to intramuscular The lesions are ill defined masses which sist (often mistakenly interpreted as true
lesions composed of both a mature vas- vary from a few centimeters to 10-20 cm. local recurrence). In some studies near-
cular and fatty component, has also in diameter. Although they vary in colour, ly 50% of patients develop multiple
been used for angiomatosis. many may have a fatty appearance, due recurrences. Metastasis or malignant
to the presence of mature adipose tis- transformation has not been reported
Epidemiology sue. Angiomatosis may assume one of {510,978,1758}.
Approximately two-thirds of cases devel- two patterns. The more common pattern These recurrence rates probably reflect
op within the first two decades of life and is that of a melange of venous, cav- incomplete excisions in the face of
nearly all are apparent by age 40 years. ernous and capillary-sized vessels scat- extensive disease.
A B
Fig. 7.09 Angiomatosis showing (A) clusters of small vessels radiating from a vein. B 1436 Note the diffuse growth pattern.
Angiomatosis 161
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A. Beham
Lymphangioma
Definition soft and fluctuant at palpation, and can fibrosis and stromal inflammation.
A benign, cavernous / cystic vascular show displacement of surrounding Stromal mast cells are common and
lesion composed of dilated lymphatic organs at mediastinal or intraabdominal haemosiderin deposition is frequently
channels. Lymphangioma circumscrip- sites. Imaging procedures like ultra- seen.
tum and progressive lymphangioma are sonography display their cystic nature,
described in the WHO classification of angiography shows poor vascularization Immunophenotype
skin tumours. and CT scan reveals multiple, homoge- The endothelium demonstrates variable
neous, nonenhancing areas. expression of FVIII-rAg, CD31 and CD34
ICD-O code 9170/0 {704}.
Aetiology
Synonym Cystic hygroma. Early or even congenital appearance in Ultrastructure
life and lesional architecture are in favour The endothelium of thin-walled vessels
Epidemiology of developmental malformations, with is not enveloped by a basement mem-
Lymphangiomas are common paediatric genetic abnormalities playing an addi- brane and no pericytes are attached to
lesions, which most often present at birth tional role. it, thus directly contacting with the inter-
or during first years of life {47,375,671, stitium. With increasing caliber the ves-
1045}. Some cases may be identified in Macroscopy sels may acquire pericytes and smooth
Turner syndrome (and other malformative Cavernous / cystic lymphangiomas cor- muscle cells, respectively.
syndromes) and may be found in abor- respond to a multicystic or spongy mass,
tuses {375}. Cavernous/cystic lymphan- the cavities of which contain watery to Genetics
gioma of head and neck represents the milky fluid. Cystic lymphangiomas ( cystic hygro-
most frequent subtype. ma") of the neck are often associated
Histopathology with Turner syndrome {289,339}.
Sites of involvement Cavernous/cystic lymphangiomas are
Cystic lymphangiomas are mostly locat- characterized by thin-walled, dilated Prognostic factors
ed in the neck, axilla and groin, whereas lymphatic vessels of different size, which Recurrences are due to incomplete
the cavernous type occurs additionally in are lined by a flattened endothelium and surgical removal, whereas malig-
the oral cavity, upper trunk, limbs and frequently surrounded by lymphocytic nant transformation does not occur.
abdominal sites including mesentery and aggregates. The lumina may be either Lymphangiomas of the neck/axilla some-
retroperitoneum {47}. empty or contain proteinaceous fluid, times extend to the mediastinum and
lymphocytes and sometimes erythro- may be of vital significance by compro-
Clinical features cytes. Larger vessels can be invested mising trachea, esophagus etc.
The lesions present as rather circum- by a smooth muscle layer, and long- Abdominal lesions can lead to intestinal
scribed painless swellings, which are standing lesions reveal interstitial obstruction.
A B
C
Fig. 7.10 A Cystic lymphangioma, collapsed. The adjacent tube shows the milky lymph removed from the lesion. B Cystic lymphangioma in the lower neck of a fetus with
Turner syndrome. C Large, partly cystic lymphangioma from mesentery and partially covered by adipose tissue.
162 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 163
A B C
Fig. 7.11 Lymphangioma. A Multiple, cystic or ectatic, thin-walled lymphatic spaces infiltrating skeletal muscle. B Cystic, dilated lymphatic spaces with accompa-
nying stromal lymphocytic aggregates, infiltrating the parotid gland in a sieve-like manner. C Thin-walled spaces of varying diameter, containing lymph and / or lym-
phocytes, and lined by flattened endothelium.
A B C
Fig. 7.12 Cavernous lymphangioma. A Note the prominent smooth muscle in the vessel walls. B There is no endothelial multilayering or atypia. C Note the cyst-like enlarg-
ments of lymphatic vessels.
W.Y.W. Tsang
Kaposiform haemangioendothelioma
Definition Site of involvement masses and may involve the underlying
Kaposiform haemangioendothelioma is a The tumour most commonly occurs in the bone and rarely regional lymph nodes
locally aggressive, immature vascular retroperitoneum {2135,2352} and the (variably interpreted as either local
neoplasm, characterized by a predomi- skin {1300,1554,2204}, but it can also extension or local metastasis) {1300}.
nant Kaposi sarcoma-like fascicular spin- occur in the head and neck region, medi- Cutaneous lesions present as ill defined
dle cell growth pattern. astinum, and deeper soft tissues of the violaceous plaques. Consumption coag-
trunk and extremities {1418,2270,2352}. ulopathy (Kasabach-Merritt syndrome)
ICD-O code 9130/1 may complicate the larger tumours due
Clinical features to activation of clotting pathways within
Synonyms Kaposiform haemangioendothelioma the tumour vasculature.
Kaposi-like infantile haemangioendothe- typically occurs in infancy and first
lioma {2135}, haemangioma with Kaposi decade of life, but adult cases are Aetiology
sarcoma-like features {1554}. increasingly recognized {1300,1418}. There is no known association with HIV
Retroperitoneal tumours usually present infection or HHV8.
Epidemiology as abdominal mass, ascites, intestinal
This is a rare tumour with no known racial obstruction, and jaundice. Deep soft tis- Macroscopy / Histopathology
predilection. sue lesions produce single or multiple Cutaneous lesions appear as ill defined,
Lymphangioma / Kaposiform haemangioendothelioma 163
bb5_12.qxd 13.9.2006 10:58 Page 164
be tumour lo-bules resembling cellular
haemangioma or capillary haeman-
gioma. There are often adjacent foci
resembling lymphangiomatosis. Fibrin
thrombi and fragmented red cells can be
found in the slit-like spaces and the cap-
illaries. There may be haemorrhage,
haemosiderin deposition and rare hya-
line globules.
A B
Immunophenotype
The spindle cells are usually negative for
Factor VIII-related antigen, but positive
for CD34 and CD31, especially those lin-
ing vascular slits. Muscle-specific actin
highlights variable numbers of spindle
cells, suggesting the presence of peri-
cytes in at least some areas.
Ultrastructure
C D
Ultrastructural hallmarks of endothelial
Fig. 7.13 Kaposiform haemangioendothelioma. A Subcutaneous lesion showing well developed lobular archi- cells are poorly developed in the spindle
tecture. B Retroperitoneal lesion in a young infant with destructive infiltration of the pancreas. C Higher mag- cells and represented by poorly formed
nification shows loosely arranged spindle cells forming vascular slits mixed with some dilated capillaries.
lumens and discontinuous basal lamina.
D Cutaneous kaposiform haemangioendothelioma with irregular, infiltrative tumour growth in the dermis.
Weibel-Palade bodies may be totally
absent.
Prognostic factors
violaceous plaques. Soft tissue tumours spaces or more loosely arranged, con- Kaposiform haemangioendothelioma
are greyish to reddish, multi-nodular, and taining slit-like, sieve-like or crescent- shows no tendency for spontaneous
may coalesce and encase surrounding shaped vascular lumens. Nuclear atypia regression {1300}. The prognosis varies
structures. and mitotic activity are usually incon- with the site and size of the lesion.
Microscopically, the tumour grows in the spicuous. Rarely, the spindle cell fasci- Outlook is poor for large tumours occur-
form of infiltrative vague lobules separat- cles may blend with round "glomeruloid" ring in infancy complicated by Kasa-
ed by fibrous septa. It consists predom- solid nests of polygonal / epithelioid bach-Merritt syndrome, especially when
inantly of criss-crossing spindle cell endothelial cells which possess abun- occurring in intraabdominal sites.
fascicles interspersed with capillaries. dant eosino-philic cytoplasm. The inter- Lesions in the somatic soft tissue are cur-
The fascicles are curved or straight, and spersed capillaries are lined by flat or able by complete excision, and recur-
may be compact with few interspersed plump endothelial cells, and there can rence appears to be rare.
A B C
Fig. 7.14 Kaposiform haemangioendothelioma. A The spindle cell fascicles are compact and are interspersed with numerous capillaries. B The spindle cells are bland-
looking. C The spindle cells and capillaries show strong reactivity with CD31.
164 Vascular tumours
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E. Calonje
Retiform haemangioendothelioma
Definition Clinical features blend with the underlying stroma.
Retiform haemangioendothelioma (RH) RH presents as a red/bluish slowly grow- Pleomorphism is absent and mitotic fig-
is a locally aggressive, rarely metasta- ing plaque or nodule usually less than 3 ures are rare. A prominent stromal and
sizing vascular lesion, characterized by cm in maximum dimension. A case with often intravascular lymphocytic infiltrate
distinctive arborizing blood vessels lined multiple lesions has been described is present in around half of the cases.
by endothelial cells with characteristic {556}. Exceptional cases occur in the The stroma surrounding the tumour
hobnail morphology. These tumours setting of previous radiotherapy or pre- tends to be sclerotic. Focal solid areas
appear to be closely related to papillary existing lymphoedema {296}. composed of sheets of endothelial cells
intralymphatic angioendothelioma. are often identified. Vacuolated cells are
Macroscopy / Histopathology uncommonly seen. Monomorphic endo-
ICD-O code 9135/1 Macroscopic examination reveals dif- thelial spindle-shaped cells are also a
fuse induration of the dermis with fre- rare feature and were described in the
Synonym quent involvement of the underlying single metastatic lymph node reported
Hobnail haemangioendothelioma. subcutaneous tissue. Scanning magnifi- {296}. In some cases there are intra-
cation reveals characteristic elongated vascular papillae with hyaline collage-
Epidemiology and narrow arborizing vascular channels nous cores similar to those seen in
RH is uncommon. Since its original with a striking resemblance to the papillary intralymphatic angioendothe-
description in 1994, only 20 cases have normal rete testis. Although this pattern lioma. Retiform haemangioendothelioma
been reported {296,734,1419}. The age is usually readily apparent, if the vascu- can be one of the components of a com-
range is wide but it usually affects young lar channels are small or collapsed, posite haemangioendothelioma (see
adults with no sex predominance. then the retiform architecture might be page 168).
difficult to recognize. Monomorphic
Sites of involvement hyperchromatic endothelial cells with Immunophenotype
The tumour involves predominantly the prominent protuberant nuclei and char- The neoplastic cells in RH stain for
skin and subcutaneous tissue and acteristic tombstone or hobnail appear- vascular markers including CD31, CD34
shows predilection for the distal extremi- ance line the blood vessels. These cells and VWF (von Willebrand factor).
ties, particularly the lower limb. have scanty cytoplasm, which seems to Staining for CD34 is often stronger
than that of other vascular markers.
Most of the lymphocytes in the infiltrate
stain for pan-T cell markers including
CD3. Only a minority of the lymphocytes
stain for the B cell marker CD20. The lat-
ter are only found in the stroma sur-
rounding the vascular channels. In gen-
eral experience these lesions are HHV-8
negative.
Prognostic factors
Multiple local recurrences (in up to 60%
of cases), often over a period of many
years, are the rule unless wide local
excision is performed {296}. So far only
one patient has been reported to devel-
op a metastasis to a regional lymph
node. A further patient developed a local
soft tissue metastasis from a primary in
the right big toe {1419}. To date, no
patients have been described to devel-
op distant metastasis or to die from this
Fig. 7.15 Retiform haemangioendothelioma. Characteristic arborizing channels simulating the rete testis and
with a prominent stromal lymphocytic infiltrate. disease.
Retiform hemangioendothelioma 165
bb5_12.qxd 13.9.2006 10:58 Page 166
A B
C D
Fig. 7.16 Retiform haemangioendothelioma. A Focal areas with a more solid growth pattern are frequent. B Typical hobnail endothelial cells with prominent nuclei.
C Vacuolated cells and (D) intraluminal papillae with collagenous cores similar to those seen in Dabska's tumour are seen in some cases.
166 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 167
E. Calonje
Papillary intralymphatic
angioendothelioma
Definition Macroscopy Immunophenotype
Papillary intralymphatic angioendothe- Tumours are ill defined and usually Staining for vascular markers in-
lioma (PILA) is a locally aggressive, rarely involve the dermis and subcutaneous cluding CD31, von Willebrand factor
metastasizing vascular lesion character- tissue. The vascular nature of the lesion and CD34 is usually positive. The
ized by lymphatic-like channels and pap- is not immediately apparent and haem- finding of strong expression of
illary endothelial proliferation. These orrhage is rare. Cystic spaces can be vascular endothelial growth facto
tumours appear to be closely related to identified in some instances. receptor-3 (VEGFR-3) by tumour cells
retiform haemangioendothelioma. in lesions with hobnail endothelial cells
Histopathology has been regarded as suggestive of
ICD-O code 9135/1 If strict diagnostic criteria are used, lymphatic differentiation {635,704}.
tumours can be described as com- However, the specificity of this marker
Synonyms posed of dilated, thin-walled vascular as an indicator of lymphatic origin is
Dabska tumour, malignant endothelial spaces often resembling a cavernous doubtful.
papillary angioendothelioma, hobnail lymphangioma {635}. In rare cases the
haemangioendothelioma. vascular channels are smaller and more Prognostic factors
irregular. Formation of prominent intralu- In the original series, a tendency for
Epidemiology minal papillary tufts with hyaline cores local recurrence and regional lymph
PILA is very rare and has predilection lined by hobnail endothelial cells is a node metastasis was suggested {419}.
for infants and children. characteristic finding. Furthermore, at least one of the
Around 25% of cases present in adults The endothelial cells lining the spaces patients in the original series died of
{635}. Sex incidence is similar. have scant pink cytoplasm and a promi- disease. However, follow-up in 8 of
nent nucleus with little or no cytological the 12 cases reported recently re-
Sites of involvement atypia and a typical hobnail or match- ported neither local recurrences nor
Most cases involve the limbs and fewer stick appearance. The hyaline cores metastatic spread {635}. Therefore,
cases present on the trunk. contain basement membrane material the issue about the malignant po-
synthesized by tumour cells. A variable tential of this tumour remains un-
Clinical features number of lymphocytes are seen within solved pending further studies. It is
PILAs present as a slowly growing asym- and around the vascular channels. advisable to excise lesions widely when
ptomatic cutaneous plaque or nodule. Mitotic figures are rare. feasible.
A BC
Fig. 7.17 Papillary intralymphatic angioendothelioma. A Cavernous lymphangioma-like spaces. B Numerous intravascular papillae with collagenous cores. C Note the
characteristic hobnail epithelium.
Papillary intralymphatic angioendothelioma 167
bb5_12.qxd 13.9.2006 10:58 Page 168
B.P. Rubin
Composite haemangioendothelioma
Definition Clinical features lioma, retiform haemangioendothelioma,
Composite haemangioendothelioma is 25% of patients with composite hae- spindle cell haemangioma, "angiosarco-
defined as a locally aggressive, rarely mangioendothelioma have a history of ma-like" areas, and benign vascular
metastasizing neoplasm with vascular lymphoedema. Lesions are usually long- lesions (arterio-venous malformation,
differentiation, containing an admixture standing (2-12 years) and have a red- and lymphangioma circumscriptum).
of histologically benign, intermediate dish-blue, variably nodular appearance. Another interesting feature, seen in sev-
and malignant components. eral cases, is the presence of large
Macroscopy numbers of vacuolated endothelial cells
ICD-O code 9130/1 Composite haemangioendothelioma which impart a pseudolipoblastic
presents as an infiltrative, uninodular or appearance. The "angiosarcoma-like"
Epidemiology multinodular mass (individual nodules areas are characterized by a low
Composite haemangioendothelioma is measure 0.7 6 cm), or as an area of ill grade angiosarcomatous appearance
an extremely rare and recently defined "swelling". Some of the lesions composed of complex dissecting
described neoplasm with less than 10 are associated with reddish purple skin vascular channels with endothelial
cases reported in the English language discoloration, suggestive of the diagno- atypia and relatively few mitotic figures.
literature {1543,1776}. Histologically sis of a vascular neoplasm. The biological significance of such
similar lesions were previously reported lesions should be determined in larger
{373}. The gender distribution is approx- Histopathology studies. Exceptionally, the "angiosarco-
imately equal and the majority of cases Composite haemangioendothelioma is a ma-like" area in a single case had the
occur in adults, although a single case poorly circumscribed, infiltrative lesion, appearance of high grade angiosarco-
which first developed in infancy has centered in the dermis and subcutis. It ma characterized by a solid growth
been described {1776}. possesses a complex admixture of pattern and numerous mitotic figures.
histologically benign and malignant The biological potential of lesions such
Sites of involvement vascular components that vary greatly as the latter remains to be determined
Most cases have shown a predilection in their relative proportions. These through study of larger case num-
for the distal extremities, especially the lesions are unified by a similar admix- bers. Lesions are positive for vascular
hands and feet, with the exception of a ture of the different components which markers (CD31, CD34, and von
single case which arose in the tongue. include epithelioid haemangioendothe- Willebrand Factor).
Fig. 7.18 Composite haemangioendothelioma pre- Fig. 7.19 Composite haemangioendothelioma. This complex lesion had areas consistent with retiform haeman-
senting as a bluish-purple multinodular mass. gioendothelioma as well as more solid areas consistent with epithelioid haemangioendothelioma.
168 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 169
A B
Fig. 7.20 Composite haemangioendothelioma. A Typical appearance of the epithelioid haemangioendothelioma component. B Sheets of vacuolated endothelial cells are
not unusual.
A B
Fig. 7.21 Composite haemangioendothelioma. A Several lesions have areas consistent with spindle cell haemangioma. B Areas consistent histologically with well-dif-
ferentiated angiosarcoma.
Prognostic factors recurrences. In the patient with the after excision of the primary, respective-
Half of the lesions recurred locally tongue lesion, metastasis occurred to a ly. Thus, the behaviour appears to be
between 4 and 10 years after excision of submandibular lymph node and to the much less aggressive than conventional
the primary mass, often with multiple soft tissue of the thigh at 9 and 11 years angiosarcoma.
Composite haemangioendothelioma 169
bb5_12.qxd 13.9.2006 10:58 Page 170
J. Lamovec
Kaposi sarcoma
S. Knuutila
Definition has been reduced with the advent of
Kaposi sarcoma (KS) is a locally aggres- highly active antiretroviral therapy
sive endothelial tumour that typically (HAART) {194}.
presents with cutaneous lesions in the
form of multiple patches, plaques or nod- Aetiology
ules but may also involve mucosal sites, The long sought-after infectious agent of
lymph nodes and visceral organs. The KS was identified in 1994 by Chang et al.
disease is uniformly associated with and was named KS-associated her-
human herpes virus 8 (HHV-8) infection. pesvirus (KSHV) or human herpesvirus
(HHV8) {332, 1505}. The virus is found in
ICD-O code 9140/3 KS cells of all epidemiological-clinical
Fig. 7.22 Esophageal and gastric involvement in vis-
forms of the disease and is detected in
ceral Kaposi sarcoma (KS).
Synonyms the peripheral blood before the develop-
Idiopathic multiple pigmented sarcoma ment of KS {763,2258}; the disease itself
of the skin, angiosarcoma multiplex, is the result of the complex interplay of
granuloma multiplex haemorrhagicum, HHV8 with immunologic, genetic and
Kaposi disease. environmental factors {587,1144}.
Epidemiology Sites of involvement
Four different clinical and epidemiologi- The most typical site of involvement by
cal forms of KS are recognized: 1. clas- KS is the skin. During the course of the
sic indolent form occurring predominant- disease or initially, mucosal membranes
ly in elderly men of Mediterranean/East (e.g. oral mucosa), lymph nodes and vis-
European descent, 2. endemic African ceral organs may be affected, some-
KS that occurs in middle-aged adults times without skin involvement. The
and children in Equatorial Africa who are involvement of a wide variety of tissues
not HIV infected, 3. iatrogenic KS and organs has been described {1008},
appearing in solid organ transplant although KS is very rarely, if ever, seen in
recipients treated with immunosuppres- skeletal muscles, brain and kidney.
sive therapy and also in patients treated
by immunosuppressive agents, notably Clinical features
corticosteroids, for various diseases Classic type of KS is characterized by
{2127}, 4. acquired immunodeficiency the appearance of purplish, reddish blue
syndrome-associated KS (AIDS KS), the or dark brown macules, plaques and
most aggressive form of the disease, nodules that may ulcerate. They are par-
found in HIV-1 infected individuals, that is ticularly frequent in distal extremities and
particularly frequent in homo- and bisex- may be accompanied by lymphoedema.
ual men. The relative risk of acquiring KS The disease is usually indolent, lymph
in the latter patients is >10,000 {800}; it node and visceral involvement occurs Fig. 7.23 Advanced skin lesions in classic KS.
A B C
Fig. 7.24 Cutaneous Kaposi sarcoma (KS). A Patch lesion. B Plaque stage lesion. C Nodular stage lesion.
170 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 171
Table 7.01
Epidemiological-clinical types of Kaposi sarcoma.
Type Risk groups Skin lesions--predilection sites Visceral involvement Course
Classic Elderly men of Mediterranean/ Lower legs Rare Indolent
East European descent
Endemic Middle-aged men and children Extremities Fairly common  adults Indolent  adults
in Equatorial Africa Frequent  children Aggressive  children
(lymph nodes)
Iatrogenic Immunosuppressed patients Lower legs Fairly common Indolent or aggressive
(post-transplant, other diseases)
AIDS-associated Younger, mainly homo- and Face, genitalia, Frequent Aggressive
bisexual HIV-1 infected men lower extremities
infrequently. Classic KS may be associat- ents as haemorrhagic nodules of various proliferation is often perivascular and
ed with haematopoetic malignancies. sizes that may coalesce. periadnexal. Endothelial cells lining the
In the endemic form of KS, the disease spaces are flattened or more oval, with
may be localized to skin and shows a Histopathology little atypia. Pre-existing blood vessels
protracted course. A variant of endemic Microscopic features of all four different may protrude into the lumen of new ves-
disease, a lymphadenopathic form in epidemiological-clinical types of KS do sels. Admixed are sparse lymphocytes
African children is rapidly progressive not differ. Early lesions of the skin dis- and plasma cells; frequently, extravasat-
and highly lethal. ease are uncharacteristic and present ed erythrocytes and deposits of hemo-
Iatrogenic KS is relatively frequent. It with subtle vascular proliferation {1827}. siderin surround the vascular structures.
develops in a few months to several In patch stage, vascular spaces are Slits lined by attenuated endothelial cells
years after the transplantation of solid increased in number, of irregular shape, between collagen bundles are also seen.
organs or immunosuppressive treatment and may dissect collagen fibres in the In some cases, there is a proliferation of
for a variety of conditions. The disease upper reticular dermis. They often run spindle or oval endothelial cells around
may resolve entirely upon withdrawal of parallel to the epidermis. The vascular pre-existing blood vessels in the dermis.
immunosuppressive treatment although
its course is somewhat unpredictable
{2127}. Patients who develop visceral
lesions may succumb to their disease
{1684}.
AIDS-related KS is the most aggressive
type of KS. In the skin, lesions are most
common on the face, genitals, and lower
extremities; oral mucosa, lymph nodes,
gastro-intestinal tract and lungs are fre-
quently involved. Lymph node and vis-
ceral disease without muco-cutaneous
A B
lesions may occur. The disease com-
monly behaves aggressively.
While skin lesions and lymphadenopathy
are obvious signs of the disease in vari-
ous types of KS, the spread into visceral
organs may be silent or symptomatic
depending on the extent and particular
location of the lesions.
Macroscopy
The lesions in the skin (patches, plaques,
C D
nodules) range in size from very small to
Fig. 7.25 A Early lesion (patch stage) in cutaneous Kaposi sarcoma (KS). B More cellular lesion in patch stage
several centimeters in diameter. The
of cutaneous KS. C Marked spindle cell and and vascular proliferation with extravasation of erythrocytes in
involvement of the mucosa, soft tissues,
early plaque stage. D Nodular KS of the skin; a collar of epidermis surrounds a densely cellular spindle cell
lymph nodes and visceral organs pres- tumour.
Kaposi sarcoma 171
bb5_12.qxd 13.9.2006 10:58 Page 172
Immunohistochemistry
The lining cells of clearly developed vas-
cular structures are usually positive for
vascular markers, while the spindle cells
consistently show positive reaction for
CD34 and commonly for CD31 but are
factor VIII negative. All cases, irrespec-
tive of epidemiologic subgroup, are HHV-
8 positive. The new marker FLI1, a
nuclear transcription factor, appears to
A B
be expressed in almost 100% of different
vascular tumours, including KS {695}.
Genetics
Little is known about cytogenetic and
molecular alterations in Kaposi sarcoma,
but growth factors, such as VEGF/VPF
and FGF most probably play an essential
role in transformation {1250,1853}.
Cell lines and primary tumours have
C D
been reported to have chromosome
Fig. 7.26 A Irregular jagged vascular spaces in KS, dissecting collagen fibers of the dermis. B Lymph- aberrations {311,1715,1838}, including
angioma-like lesions are uncommon and morphologically deceptive. Note the accompanying plasma cells.
gain of 8q and 1q and loss of 3p, and
C Angiomatous component in KS lesion of the skin (plaque stage). D High power view of nodular KS lesion;
rearrangements of 7q22, 8p11, 13q11
several hyaline bodies are seen.
and 19q13. A comparative genomic
hybridization (CGH) study of seven
Slit-like spaces, lymphocyte and plasma mitoses. Hyaline globules are present cases could not confirm these findings,
cell infiltration and extravasated erythro- inside and outside the spindle cells. but showed recurrent gains at 11q13
cytes are also observed. Some patients, usually with endemic {1130}. Further investigation suggested
In plaque stage, all characteristics of nodular type KS, develop lesions which that the target genes in the amplified
patch stage are exaggerated. There is closely resemble lymphangioma. area are FGF4 and FGF3 (a.k.a. INT2).
more extensive angio-proliferation with In lymph nodes, the infiltrate may be uni- Also KRAS2 and TP53 rearrangements
vascular spaces showing jagged out- or multifocal and the lymph node may be were reported {1553,1904}.
lines. Inflammatory infiltrate is denser entirely effaced by tumour. Early lesions
and extravascular red cells and may be subtle, showing only increased Prognostic factors
siderophages are numerous. Hyaline number of vascular channels accompa- The evolution of disease depends on the
globules (likely representing destroyed nied by plasma cell infiltration {1287}. In epidemiological-clinical type of KS and
red blood cells) are frequently found. visceral organs, the lesions tend to on its clinical extent. It is also modified by
Nodular stage is characterized by well respect architecture of the organs treatment that includes surgery, radio-
defined nodules of intersecting fascicles involved and spread along vascular and chemotherapy. Cases with wide-
of spindle cells with only mild atypia and structures, bronchi, portal areas in the spread visceral involvement are com-
numerous slit-like spaces containing red liver, etc., and from these sites they monly poorly responsive to treatment.
cells. Peripherally, there are ectatic blood involve surrounding parenchyma {631,
vessels. Many spindle cells show 1008}.
A B
Fig. 7.27 A CD34 positive reaction of KS cells in nodular skin disease. B Nuclear immunopositivity for HHV-8 is
a consistent finding in all histologic types and clinical subsets of Kaposi sarcoma.
172 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 173
B.P. Rubin
Other intermediate vascular neoplasms
W.Y.W. Tsang
C.D.M. Fletcher
The Working Group also considered two no clear diagnostic criteria and there As yet, it is not certain that this is prima-
other tumours for possible inclusion in are uncertainties regarding biological rily an endothelial tumour.
the new WHO classification  polymor- potential. Polymorphous haemangioendothelioma,
phous haemangioendothelioma and Giant cell angioblastoma, of which 4 of which less than ten cases have been
giant cell angioblastoma  but decided cases have been reported, arises in soft reported, may primarily involve soft tis-
that available data are insufficient to tissue of infants, is comprised of nodular sue or lymph nodes, affects adults, has
allow definitive classification of these aggregates of histiocytoid cells arranged complex and worrisome morphologic
lesions. Specifically, very few cases have around bland angiomatous vessels and features and metastasizes in some cases
been reported to date, there are as yet may show persistent growth {808,2193}. {327,1537,1771}.
S.W. Weiss
Epithelioid haemangioendothelioma
J.A. Bridge
Definition the extremities. Nearly one half to two- lesion may arise from a large vein or
Epithelioid haemangioendothelioma is an thirds originate from a vessel, usually a artery in which case it presents as an
angiocentric vascular tumour with small vein. In exceptional cases the entirely intraluminal mass.
metastatic potential, composed of
epithelioid endothelial cells arranged in
short cords and nests set in a distinctive
myxohyaline stroma.
ICD-O code 9133/3
Synonyms
Intravascular bronchioloalveolar tumour,
angioglomoid tumour, myxoid angioblas-
tomatosis.
Epidemiology
Epithelioid haemangioendothelioma is a
rare vascular tumour although its precise
incidence has never been determined.
The lesion occurs in nearly all age
groups with the exception of the early
childhood years and affects the sexes
equally {1407, 2238, 2245}.
Sites of involvement
The tumour develops as a solitary tumour
Fig. 7.28 Epithelioid haemangioendothelioma involving the lumen of a small vein and extending into adja-
in either superficial or deep soft tissue of cent tissue. Origin from a vessel is evident in approximately 30% of cases.
Other intermediate vascular neoplasms / Epithelioid haemangioendothelioma 173
bb5_12.qxd 13.9.2006 10:58 Page 174
Clinical features
The tumour develops as an often painful
nodule in either superficial or deep soft
tissue. Because of its origin from a vessel
there may be associated symptoms of
oedema or thrombophlebitis. Deeply sit-
uated tumours may be associated with
focal ossification which can be detected
on plain films. Although an association
with oral contraceptives has been raised
A B
with respect to hepatic forms of the dis-
Fig. 7.29 Epithelioid haemangioendothelioma (A,B). Note the typical strand or cord-like pattern.
ease, no such association has been doc-
umented with soft tissue variants.
Macroscopy blister their contours. Seldom do they Immunohistochemistry /
In its classic form, epithelioid haeman- produce multicellular vascular channels Ultrastructure
gioendothelioma arises as a fusiform as may be seen in epithelioid heman- A variety of vascular antigens can be
intravascular mass which may resemble giomas. The cells appear quite bland identified within epithelioid haeman-
an organizing thrombus except for the with little or no mitotic activity. The neo- gioendothelioma but CD31, CD34 and
fact that it appears matted down and plastic epithelioid endothelial cells are FLI1 are more sensitive and more reliable
infiltrative of surrounding structures. embedded in a distinctive, sulfated acid- markers than von Willebrand factor.
rich matrix which varies from a light blue Focal cytokeratin expression is noted in
Histopathology (chondroid-like) to a deep pink (hyaline) about 25-30% of cases. By electron
In small or early tumours, the lesion colour. Metaplastic bone is occasionally microscopy the neoplastic cells are situ-
expands the originating vessel, preser- present within large deep lesions and ated on a distinct basal lamina, possess
ving its architecture as its extends some cases contain prominent osteo- surface-oriented pinocytotic vesicles,
centrifugally into soft tissue. The lumen clastic giant cells. and occasional Weibel-Palade bodies.
is filled with necrotic debris and dense Approximately one third of epithelioid They differ from normal endothelium by
collagen. Tumours are composed of haemangioendotheliomas show atypical the abundance of intermediate (vimentin)
short strands, cords, or solid nests histologic features which confer a more filaments.
of rounded to slightly spindled aggressive course. These include
eosinophilic endothelial cells which marked nuclear atypia, mitotic activity Genetics
have been referred to as "epithelioid" or (>1/10 HPF), spindling of the cells, and An identical translocation involving chro-
"histiocytoid." These cells display necrosis. These features justify the des- mosomes 1 and 3 [t(1;3)(p36.3;q25)] has
endothelial differentiation primarily at ignation "malignant epithelioid haeman- been reported in two of three cytogeneti-
the cellular level as evidenced by gioendothelioma". Some cases represent cally analysed soft tissue epithelioid hae-
intracytoplasmic lumina (vacuoles) con- a morphological continuum with epithe- mangioendotheliomas, possibly repre-
taining erythrocytes which distort or lioid angiosarcoma. senting a characteristic rearrangement
for this entity {232,1403}.
Prognosis and prognostic factors
The behaviour of epithelioid haeman-
gioendothelioma is intermediate
between haemangiomas and conven-
tional (high grade) angiosarcomas,
although the actual mortality figures are
greatly influenced by inclusion of cases
with atypical or malignant features in any
given series. Based on studies which
include both classic and malignant
epithelioid haemangioendotheliomas
{1407,2238,2245} the local recurrence
rate is 10-15%, metastatic rate 20-30%,
and mortality 10-20%. Separate analysis
of classic epithelioid haemangioendothe-
lioma lacking atypical histological fea-
tures has a metastatic rate of 17% and
mortality of 3% {2245}. Atypical morpho-
logical features (described above) corre-
Fig. 7.30 Partial G-banded karyotype illustrating the t(1;3)(p36.3;q25) in epithelioid haemangioendothelioma. late with an increased risk of metastases.
174 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 175
A B
Fig. 7.31 Epithelioid haemangioendothelioma. Note (A) the myxoid matrix and (B) intracytoplasmic lumina.
Fig. 7.32 Ultrastructure showing a prominent linear
arrangement of pinocytotic vesicles and electron
dense Weibel-Palade bodies.
S.W. Weiss
Angiosarcoma of soft tissue
J. Lasota
M.M. Miettinen
Definition Sites of involvement patients with Klippel-Trenaunay and
Angiosarcoma is a malignant tumour the Most lesions occur in the deep muscles Maffucci syndromes, and following radia-
cells of which variably recapitulate the of the lower extremities (about 40%) fol- tion for various types of malignancies.
morphologic and functional features of lowed by the arm, trunk and head and
normal endothelium. neck. A significant proportion arise in the Macroscopy / Histopathology
abdominal cavity. Rarely the lesions are These lesions are multinodular haemor-
ICD-O code 9120/3 multifocal. rhagic masses that range in size from a
few centimeters to several centimeters in
Synonyms Clinical features diameter. They vary in appearance from
Lymphangiosarcoma, haemangiosarco- Soft tissue angiosarcomas develop as spindle to epithelioid neoplasms. Thus,
ma, haemangioblastoma, malignant hae- enlarging masses which in one third of at one extreme an angiosarcoma may
mangioendothelioma, malignant angio- patients are also associated with other resemble a fibrosarcoma or Kaposi sar-
endothelioma. symptoms such as coagulopathy, coma or at the other extreme an undiffer-
anaemia, persistent haematoma, or entiated carcinoma. Angiosarcomas with
Incidence bruisability. In very young patients high either one of these extreme appearances
Angiosarcomas are rare sarcomas the output cardiac failure from arteriovenous may be very difficult to diagnose on light
majority of which develop as cutaneous shunting or even massive haemorrhage microscopy without the benefit of ancil-
tumours sometimes associated with lym- may be observed. About one third of lary studies (see below). Generally
phedema (see Skin volume). Less than patients develop these tumours in asso- angiosarcomas in soft tissue have both
one quarter present as a deep soft tissue ciation with certain pre-existing condi- epithelioid and spindled areas with an
mass {1387, 2244}. tions suggesting several pathogenetic emphasis on the former. Epithelioid areas
mechanisms in the development of this are made up of large rounded cells of rel-
Epidemiology form of angiosarcoma. For example, soft atively high nuclear grade which are
Unlike cutaneous angiosarcomas, soft tissue angiosarcomas have been report- arranged in sheets, small nests, cords or
tissue angiosarcomas are more evenly ed within benign or malignant nerve rudimentary vascular channels. The
distributed throughout the decades with sheath tumours associated with neurofi- diagnosis of angiosarcoma is suspected
a peak incidence in the 7th decade. bromatosis (NF1), adjacent to synthetic on light microscopy by identifying cells
Angiosarcomas occurring in childhood, vascular grafts or other foreign material, forming rudimentary vascular channels.
however, are very rare. in rare benign haemangiomas, in Unlike normal vascular channels, these
Epithelioid haemangioendothelioma / Angiosarcoma of soft tissue 175
bb5_12.qxd 13.9.2006 10:58 Page 176
A B
Fig. 7.33 Angiosarcoma (A,B). Many cases in soft tissue have predominantly epithelioid cytomorphology with variably solid or vasoformative architecture.
neoplastic channels are irregular in but the overall diagnosis should usually angiosarcoma, particularly for poorly dif-
shape, freely intercommunicate with one reflect the diagnosis of a high grade ferentiated forms in which vascular chan-
another in a sinusoidal fashion, and infil- angiosarcoma. nel formation is difficult to identify.
trate surrounding tissues in a destructive Angiosarcomas express to a greater or
fashion. In some areas the vessels may Epithelioid angiosarcoma lesser degree the usual vascular anti-
be lined by a single attenuated layer of Epithelioid angiosarcoma is a variant of gens including von Willebrand factor,
neoplastic endothelium resembling a angiosarcoma composed predominantly CD31, and CD34. Although von
haemangioma while in other areas the or exclusively of large rounded "epithe- Willebrand factor is the most specific of
vascular channels are lined by a surfeit lioid" endothelial cells with abundant the vascular markers, it is also the least
of neoplastic endothelium forming intra- amphophilic or eosinophilic cytoplasm sensitive, often present in only a minority
luminal buds, projections or papillae. and large vesicular nuclei {681}. of angiosarcomas as focal weak staining.
Extensive haemorrhage is a characteris- Architecturally the cells are arranged in CD31, on the other hand, combines both
tic feature of most tumours, and, in the the patterns described above. Although relative specificity with excellent sensitiv-
extreme case, a haemorrhagic soft tissue these lesions may occur as cutaneous ity and is positive in approximately 90%
angiosarcoma may masquerade as a tumours, most segregate in deep soft tis- of angiosarcomas of all types {477,
chronic haematoma. sue. Many cases express cytokeratin 2244}. Cytokeratin is present in about
The majority of soft tissue angiosarco- along with endothelial markers. Their one third of soft tissue angiosarcomas,
mas are high grade tumours character- principal significance is the close mimic- particularly in the epithelioid forms,
ized by cells of high nuclear grade dis- ry they provide with carcinoma. reflecting the fact that cytokeratin cannot
playing mitotic activity. In occasional be used as an absolute discriminant
cases, however, areas with low grade, Immunohistochemistry between angiosarcoma and carcinoma.
sometimes epithelioid morphology may Immunohistochemistry is an important Although not regarded as "first line" anti-
be observed. These areas can be noted, adjunctive procedure in the diagnosis of gens, in the diagnosis of angiosarcomas,
A B
Fig. 7.34 Angiosarcoma (A,B). These lesions show more obvious vasoformative growth with complex anastomosing channels.
176 Vascular tumours
bb5_12.qxd 13.9.2006 10:58 Page 177
laminin and Type IV collagen can be
detected around neoplastic vascular
channels and, therefore, can been used
to accentuate vascular channel forma-
tion not readily apparent by light
microscopy. Actin likewise identifies per-
icytes which partially invest the vascular
channels in angiosarcomas. In general
experience angiosarcomas are consis-
tently HHV-8 negative.
Ultrastructure
In better differentiated areas of angiosar-
coma, clusters of neoplastic cells sur-
rounded by basal lamina and occasional
pericytes can be identified. The neoplas-
tic cells are joined by junctional attach- A
ments and possess abundant intermedi-
ate filaments, sparse to moderate rough
endoplasmic reticulum mitochondria and
Golgi apparatus, and have surface ori-
ented pinocytotic vesicles. Weibel-
Palade bodies, a specific tubular
organelle of normal endothelium, are
only rarely identified {1387}.
Genetics
Genetic studies of soft tissue angiosar-
comas are scant and limited to isolated
cases.
Almost all reported angiosarcoma
karyotypes have shown complex cytoge-
netic aberrations {320,787,929,1120,
1489,1896,2293,2349}. The only excep-
B
tion is a karyotype obtained from
Fig. 7.35 Angiosarcoma (A,B). Note endothelial papillae and the dissecting growth pattern.
angiosarcoma arising in cavernous
haemangioma, showing trisomy 5 and
loss of the Y as the sole cytogenetic from different locations revealed simi- also reported in sporadic skin / soft tis-
abnormalities {1321}. No consistent, larities. Among the most common sue and parenchymal angiosarcomas
recurring chromosomal abnormality has changes were gains of 5pter-p11, 8p12- {1527,1734,1981,2344}. An alteration of
yet been identified. However, some cyto- qter, 20pter-q12 and losses of 4p, 7p15- the TP53 / MDM2 pathway with elevated
genetic changes reported in tumours pter, -Y and abnormalities involving 22q expression of TP53 and MDM2 proteins
{320, 787, 929, 1120, 1321, 1896, 2293, was documented in 60% of angiosarco-
2349}. mas {2344}.
Flow cytometric DNA studies have
shown diploid, tetraploid and aneuploid Prognostic factors
patterns {521, 614, 739}. No significant Soft tissue angiosarcomas are highly
correlation between clinical outcome and aggressive tumours. Local recurrences
DNA ploidy pattern has been reported develop in about one fifth of patients and
{521,614,739}. one half may be expected to die within
Association between exposure to thorium the first year after diagnosis with
dioxide or vinyl chloride and develop- metastatic disease in the lung followed
ment of liver angiosarcoma is well by lymph node, bone, and soft tissue.
known. Specific KRAS2 and TP53 muta- The features which have been statistical-
tions were identified in these tumours ly correlated with poor outcome include
Fig. 7.36 High grade angiosarcoma with epithelioid
{963, 1330,1331,1527,1734,1981,2129}. older age, retroperitoneal location, large
features showing an ill-formed vessel lined by plump
endothelial cells and containing erythrocytes. Similar KRAS2 and TP53 mutations were size, and high Ki-67 values {1387}.
Angiosarcoma of soft tissue 177