Case Report
Primary pulmonary epithelioid angiosarcoma presenting as asolitary pulmonary nodule on imagepin_2809 424..428
Chun-Fan Yang, Tsung-Wei Chen, Guan-Chin Tseng and I-Ping Chiang
Department of Pathology, China Medical University Hospital, Taichung, Taiwan
Primary angiosarcoma of lung is a rare condition. Onlyabout 20 cases have appeared in English published reportsso far. Its rarity and consequent low index of suspicionmakes clinical diagnosis difficult. Pathological diagnosis ofthe epithelioid variant of pulmonary angiosarcoma is par-ticularly challenging. We report a case of primary pulmo-nary epithelioid angiosarcoma as a solitary pulmonarynodule in image study in a 41-year-old man with a briefreview, to contribute it to the sparse literature on thisdisease.
Key words: angiosarcoma, epithelioid, lung, pathology,pulmonary
INTRODUCTION
Pulmonary angiosarcomas are almost always metastaticmalignancies from other primary sites. As for primary pulmo-nary angiosarcomas, only about 20 reports exist in English.Primary pulmonary angiosarcomas are characterized byinsidious growth and extensive local invasion by the time ofdiagnosis. Since the primary pulmonary angiosarcoma is rareand usually not considered a priority, diagnosis is usuallydelayed until the possibility of other primary locus has beenexcluded.
Classical angiosarcomas always show vasoformative fea-tures. The challenge of diagnosis is, however, its epitheliodvariant. Stepphard et al. have reported a case of primarypulmonary epithelioid angiosarcoma among the earliestreports published in English about pulmonary angiosar-coma.1 Epithelioid differentiation is believed to be a feature of
higher malignant potential as compared with classical ones.The pulmonary epithelioid angiosarcoma is easily misdiag-nosed as other high-grade or anaplastic carcinomas in thelung. The microscopic feature is sometimes misleadingexcept some subtle clues like RBC containing intracytoplas-mic luminas. Diagnosis depends greatly on immunohis-tochemical analysis for endothelial markers including vonWillebrand factor, CD34, CD31, Ulex europaeus agglutinin I,factor VIII related antigens, Fli1 and more.
CLINICAL SUMMARY
Our case is a 41-year-old male farmer with history of hyper-tension and end-stage renal disease (ESRD) under continu-ous ambulatory peritoneal dialysis (CAPD) treatment. Hewas found to have a 1.4-cm solitary pulmonary nodule bychest X-ray during regular follow-up for his ESRD. The sub-sequent chest computed tomography (CT) scan revealed a1.7-cm nodule with bilobulation in the apicoposterior segmentof left upper lobe of lung, as well as an enlarged lymph node(greater than 1 cm in its short-axis diameter) at right subcari-nal region (Fig. 1; arrow). The result of positron emissiontomography (PET) is matched with that in systemic CT scan.
The patient had been well except complaints about pro-ductive cough with yellowish thick sputum for a long time. Hedenied blood-tinged sputum. Generalized physical examina-tion did not reveal mass lesion over extremities and trunk.There were findings of suspected polycystic kidney diseaseand horseshoe kidney on abdominal CT images. Because ofthe limited credibility of endobronchial-ultrasonographically-guided biopsy for peripheral pulmonary lesions, thoraco-scopic wedge resection and lymph node sampling wasplanned to determine the nature of this tumor.
Intra-operative biopsy for frozen section examination dis-closed a high-grade pleomorphic malignancy of undeter-mined phenotype composed of sheets of large round, oval toelongated spindled cells with abundant eosinophilic cyto-plasm, distinct nucleoli, scattered tumor monster/giant cells
Correspondence: Tsung-Wei Chen, MD, Department of Pathology,China Medical University Hospital, Taichung 40447, Taiwan. Email:[email protected]
Received 22 December 2011. Accepted for publication 3 February2012.© 2012 The AuthorsPathology International © 2012 Japanese Society of Pathology andBlackwell Publishing Asia Pty Ltd
Pathology International 2012; 62: 424–428 doi:10.1111/j.1440-1827.2012.02809.x
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Figure 1 Chest computed tomography (CT) scan reveals a 1.7-cmsolitary pulmonary nodule with bilobulation in the apicoposteriorsegment of left upper lobe of lung.
Figure 2 The lung tumor appears as a well-defined whitish and firmtumor with slight hemorrhage.
a b
c d
Figure 3 (a) 200¥ H&E stain. The tumor showed a high-grade tumor with marked nuclear pleomorphism. (b) 400¥ H&E stain. The tumor iscomposed of large epithelioid or elongated tumor cells with vesicular nuclei, distinct nucleoli, frequent mitotic figures and abundant pale toeosinophilic cytoplasm. (c) 400¥ H&E stain. Frequent intracytoplasmic vacuoles containing extravasated erythrocytes. (d) 200¥ Immunohis-tochemical stain of CD31 and CD34 (not shown here) was diffusely positive in the tumor cells.
Pulmonary epithelioid angiosarcoma 425
© 2012 The AuthorsPathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd
and patchy tumor necrosis. Poorly differentiated non-smallcell carcinoma of the lung primary was first considered. Then,the planned operations were completed as wedge resectionof the pulmonary tumor and lymph node sampling for furtherparaffin section examinations.
Unfortunately, the patient died of septic shock and multipleorgan failure due to uncontrollable postoperative sepsisseveral days after the pulmonary surgery. Postmortemautopsy was suggested but the patient’s family refused it.
PATHOLOGICAL FINDINGS
The tumor appeared as a well-defined whitish and firm tumorwith bilobulation and slight hemorrhage (Fig. 2). The micro-scopic examination revealed a high-grade tumor composedof alternating epithelioid and sarcomatous regions withmarked nuclear pleomorphism, large vesicular nuclei withdistinct nucleoli, frequent typical and atypical mitotic figures,abundant pale to eosinophilic cytoplasm and frequent intra-cytoplasmic vacuoles (Fig. 3a–c). The immunohistochemicalstain indicated that these tumor cells were reactive for vimen-tin, CD34 and CD31 (Fig. 3d). The other stains includingCK5, CK7, CK20, TTF-1, Napsin-A, cytokeratin (AE1/AE3),CK8, HMB-45, synaptophysin, CD68, LCA, desmin, smoothmuscle actin of clone 851, CD99, EMA and S-100 proteinwere all negative. The clone, source and dilution of antibod-ies of immunohistochemical stains are listed in Table 1, aswell as the results of stains. (Table 1)
The final diagnosis of primary pulmonary epithelioidangiosarcoma was made because of the histological features
and absence of other primary site in this case. The dissectedmediastinal lymph node was negative for tumor.
DISCUSSION
Angiosarcoma is a rare malignant tumor derived from vascu-lar endothelium. It accounts for about 1–2% of all soft tissuetumors.2 Soft tissue and skin is the commonest primarysite. As for the visceral organs, heart (mostly right atrium),liver and spleen are the most common presented sites.3
Etiology includes exposure to chemical agents like thoro-trast, polyvinyl choloride, phenylethylhydrazine and coppermining dust.2–4 Post-mastectomy irradiation is also a well-established risk factor.
Pulmonary angiosarcomas are almost always metastaticmalignancies from other primary sites. There are only about20 English reports detailing the primary pulmonary angiosa-rcomas so far.3,5 Predisposing factors are unknown, but maybe related to certain stimulating factors, such as Lumciteplombage, chronic empyema and tuberculous pyothorax.6 Aslightly higher incidence is noted in middle-aged men.7
Primary pulmonary angiosarcomas are characterized byinsidious growth and extensive local invasion by the time ofdiagnosis. Since the primary pulmonary angiosarcoma is rareand usually not considered a priority, diagnosis is usuallydelayed until the possibility of other primary has beenexcluded.
Primary and metastatic pulmonary angiosarcomas havesimilar symptomatic and radiographic features.7 Hemoptysisis the most frequent symptom.8 Nonspecific symptoms andsigns, such as cough, dyspnea and pleuritic chest pain, arealso described frequently. There are also unusual symptomssuch as spontaneous recurrent hemothorax9 and shoulderpain10 in some reports.
The common radiographic presentation may be multipleperipheral pulmonary nodules, solitary mass (particular asprimary)11 with adjacent alveolar pattern and/or variabledegree of consolidation and ground-glass opacity (related tointra-alveolar hemorrhage). However, in our case, the tumorshows a pure solitary pulmonary nodule, which was anunusual finding as compared with previous reports. Overall,the radiographic feature is nonspecific and difficult to bedistinguished from other metastatic tumors.
In our case and literature review, we have noticed that theprimary angiosarcoma of lung tends to be epithelioid variantother than classical histological pattern although the exactreason is unknown. To facilitate readers with a rapid glance ofthe published reported cases, we have summarized theirindividual characters in a tabulated form, including thepatients’ age, gender, presenting symptoms/signs, imagefindings, pathological diagnosis and treatment of eachpatient (Table 2). The first 11 articles (11 patients)1,3,4,6–15 in
Table 1 Antibodies used in immunohistochemistry (source: LeicaBiosystems)
Antibody to Clone Dilution Results
CK (AE1/AE3) AE1/AE3 1:800 -CK5 XM26 1:200 -CK7 RN7 1:200 -CK8 TS1 1:600 -CK20 PW31 1:100 -EMA GP1.4 1:200 -Vimentin V9 1:400 +TTF-1 SPT24 1:400 -Napsin-A IP64 1:400 -LCA (CD45) RP2/18, RP2/22 1:200 -SMA asm-1 1:100 -Desmin DE-R-11 1:200 -CD99 12E7 1:200 -S-100 Polyclonal 1:400 -CD34 QBEnd/10 1:400 +CD31 1A10 1:100 +CD68 KP1 1:800 -Synaptophysin 27G12 1:200 -HMB-45 HMB45 1:100 -
CK, cytokeratin; LCA, leukocyte common antigen; SMA, smoothmuscle actin.
426 C.-F. Yang et al.
© 2012 The AuthorsPathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd
Tab
le2
Rep
orte
dar
ticle
sof
pulm
onar
yan
gios
arco
ma
Art
icle
†A
gean
dge
nder
Pre
sent
ing
sym
ptom
/sig
nsIm
age
(CT
)P
atho
logi
cal
diag
nosi
sTr
eatm
ent
Out
com
e
1.S
tepp
hard
65�
Hem
opty
sis
Bila
tera
lmul
tinod
ular
infil
trat
ion
EA
Pal
liativ
eth
erap
yD
ied
2da
ysaf
ter
diag
nosi
s2.
Mag
lara
s46
�H
emop
tysi
s,B
rain
and
liver
met
asta
ses
Con
solid
atio
nin
RU
Lan
ddi
ffuse
GG
Oin
bila
tera
llow
erlu
ngE
AC
hem
othe
rapy
with
Adr
iam
ycin
and
ifosf
amid
eS
hort
-ter
mre
mis
sion
ofhe
mop
tysi
sfo
llow
edby
dete
riora
tion
and
died
with
in3
mon
ths
3.P
andi
t79
�D
yspn
eaan
dpl
eurit
icch
est
pain
Mul
tiple
nodu
les
inbo
thlu
ngs
with
surr
ound
ing
grou
nd-g
lass
hazz
ines
s
EA
Pat
ient
refu
sed
ther
apy
Die
dof
resp
irato
ryfa
ilure
1.5
year
saf
ter
diag
nosi
s
4.P
atsi
os78
�H
emop
tysi
sS
oft
tissu
ede
nsity
inbe
twee
nLu
mci
tepl
omba
geE
AR
UL
lobe
ctom
yw
ithLu
mci
tepl
omba
gere
mov
alD
ied
ofse
ptic
shoc
kse
cond
ary
torig
ht-s
ided
hem
orrh
agic
empy
ema
1m
onth
afte
rdi
scha
rge
5.O
zcel
ik62
�H
emop
tysi
s,co
ugh,
ches
tpa
in3.
5cm
RU
Lno
dule
surr
ound
edby
thic
kene
d,irr
egul
arlu
ngin
ters
titiu
m
EA
Lobe
ctom
yw
ithm
edia
stin
alLN
diss
ectio
n,fo
llow
edby
chem
othe
rapy
and
radi
atio
nth
erap
y
Ref
usal
ofsu
bseq
uent
adju
vant
ther
apy
and
died
5m
onth
sla
ter
6.W
ilson
56�
Hem
opty
sis
3.9
cmm
ass
inLU
LE
ALo
bect
omy
with
LNdi
ssec
tion,
follo
wed
byra
diat
ion
ther
apy
Die
d39
mon
ths
late
raf
ter
diag
nosi
sdu
eto
nore
spon
seto
salv
age
ther
apy
7.C
ampi
one
85�
Spo
ntan
eous
recu
rren
the
mot
hora
x
Ble
edin
gfr
oma
smal
lint
rath
orac
icve
ssel
EA
Wed
gere
sect
ion
ofin
farc
ted
lung
,ad
juva
ntch
emot
hera
pyno
tdo
nedu
eto
adva
nced
age
Die
d3
mon
ths
late
rin
anot
her
hosp
ital
8.K
urod
a43
�C
ough
Hug
em
ass
inLL
LE
ALL
Llo
bect
omy
Une
vent
ful1
5m
onth
saf
ter
oper
atio
n9.
Car
illo
56�
Hem
opty
sis
2.5
cmno
dule
inLL
LE
AC
hem
othe
rapy
with
Adi
amyc
in+
ifosf
amid
efo
rpl
eura
lmet
asta
ses
Mul
tiple
recu
rren
ce/m
etas
tasi
sin
lung
two
mon
ths
late
ran
ddi
edse
ven
mon
ths
afte
rdi
agno
sis
10.
Wan
Mus
a23
�Le
ft-si
ded
shou
lder
and
ches
tpa
inH
uge
5.0
cmm
ass
inle
ftlu
ngw
ithlu
ngco
llaps
e,pl
eura
leffu
sion
and
C6
vert
ebra
met
asta
sis
EA
Che
mot
hera
pyD
ied
4m
onth
sla
ter
afte
rin
itial
pres
enta
tion
ofsh
ould
erpa
in
11.
Our
case
41�
Cou
gh1.
7cm
solit
ary
nodu
lein
LUL
EA
Wed
gere
sect
ion
with
LNdi
ssec
tion
Die
dse
vera
lday
saf
ter
oper
atio
ndu
eto
sept
icsh
ock
12.
Koj
ima
58�
Left
ches
tpa
inan
ddr
yco
ugh
5.5
cmle
fthi
lar
lung
mas
sw
ithm
edia
stin
alin
vasi
onA
Rad
iatio
nth
erap
yw
ithre
com
bina
ntin
terle
ukin
-2(r
IL-2
)N
oev
iden
ceof
loca
lrec
urre
nce
orm
etas
tasi
sfo
r1
year
afte
rdi
agno
sis
13.
Che
n50
�H
emop
tysi
sM
ultip
leno
dule
sin
left
lung
ALL
Lan
din
sula
rlo
belo
bect
omy,
follo
wed
bych
emot
hera
pyS
tilli
nfo
llow
-up
byth
etim
eof
artic
lepu
blic
atio
n14
.E
ichn
er69
�P
rogr
essi
vedy
spno
eaan
dhe
mop
tysi
s
Zon
ally
dist
ribut
ed,
mix
edre
ticul
aran
dal
veol
arat
tenu
atio
npa
ttern
inbo
thlu
ngs
AN
ofu
rthe
rtr
eatm
ent
exce
ptex
cisi
onal
biop
sydu
eto
patie
nt’s
deat
h
Die
d4
days
late
rdu
eto
resp
irato
ryan
dci
rcul
ator
yfa
ilure
81�
Spo
ntan
eous
bila
tera
lhe
mot
hora
x
Diff
use
bila
tera
linfi
ltrat
esan
dpl
eura
leffu
sion
sA
Con
firm
edby
post
mor
tem
auto
psy
Die
din
sept
icm
ultis
yste
mor
gan
failu
re3
wee
ksaf
ter
adm
issi
on
†Lis
ted
byth
eor
der
ofpu
blis
hed
year
s.A
,an
gios
arco
ma;
CT,
com
pute
dto
mog
raph
y;E
A,
epith
elio
idan
gios
arco
ma;
GG
O,
grou
nd-g
lass
opac
ity;
LLL,
left
low
erlo
be;
LUL,
left
uppe
rlo
be;
LN,
lym
phno
de;
RU
L,rig
htup
per
lobe
.
Pulmonary epithelioid angiosarcoma 427
© 2012 The AuthorsPathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd
Table 2, including our current case, demonstrated features ofepithelioid variant, whereas the other three articles (fourpatients)3,11,15 did not.
Classical angiosarcomas always show vasoformative fea-tures as anastomosing vascular channels lined by malignantendothelium. However, its epitheliod variant is characterizedby solid-sheeted growth pattern with large epithelioid orspindled tumor cells with abundant eosinophilic cytoplasm,large vesicular highly-pleomorphic nuclei and prominentnucleoli. Numerous intracytoplasmic luminas with extrava-sated red blood cells can usually be seen. Vascular channelformation is limited to a small proportion in the epithelioidvariant. Stepphard et al. have reported a case of primarypulmonary epithelioid angiosarcoma among the earliestEnglish published reports about pulmonary angiosarcoma.1
Epithelioid differentiation is believed to be a feature of highermalignant potential as compared with classical vasoformativeangiosarcoma. The pulmonary epithelioid angiosarcoma iseasily misdiagnosed as other high-grade or anaplastic carci-nomas in the lung. The microscopic feature is alwaysmisleading except some subtle clues like RBC contain-ing intracytoplasmic luminas. Diagnosis depends greatlyon immunohistochemical analysis for endothelial markersincluding von Willebrand factor, CD34, CD31, Ulex euro-paeus agglutinin I, factor VIII related antigens, Fli1, etc. Theexpression of cytokeratin or EMA is variable and also mis-leading. The presence of Weibel Palade bodies and pinocyticvesicles is also detectable on electron microscopy, althoughit is seldom used as an early diagnostic method.
Little is known about the cytogenetic or chromosomalfeature of primary pulmonary epithelioid angiosarcoma.However, Cao et al. have presented a cytogenetic com-parison between two cases of epithelioid angiosarcomaand epithelioid hemangioendothelioma, which may provideanother direction for future research.16
There is no standard treatment regimen specifically forpulmonary epithelioid angiosarcoma. Surgical excision tendsto be used for localized disease. Because the angiosarcoma,whether the extrapulmonoary or intrapulmonary one, is sus-ceptible to ionizing radiation, radiotherapy can be used forlocally advanced disease. Chemotherapy has been reportedeffective with the combined regimen of doxorubicin, vincris-tine, cyclophosphamide, dacarbazine and methotrexate.5
Recombinant interleukin-2 has also been used in a patientthat has achieved dramatic remission,15 although there is stillargument by other authors.17 Wilson et al. has mentionedcomplete radiographic response of disease by a chemothera-
peutic combination of Gemcitabine and Taxotere.13 However,none of them are shown to be really effective. The prognosisis still poor with a survival ranging about 1–9 months afterinitial diagnosis.
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