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:twchen01@gmail.com

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.

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© 2012 The AuthorsPathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

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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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