onal Aen Css Os 2010 TSS, 138439 CASE REPORT Primary pleural haemangioendothelioma in an Italian female patient: a case report and review of the literature M. Bocchino’, E. Barra?, F. Lassandro®, F. Ranieri¢, R. Muto9, G. Rea ABSTRACT: Primary pleural karmangioendothelioma in sex lialian female patient: a case repart aad review of the literature. id. Bocchino, E. Barra, F. Lassandro, R. Ranieri, R. Muto, G. Rea. Primary epithelioid haemangigendothelioma (EHE) ‘of the pleura is rare vascular tumour that occurs main- ly in men, Pleural effusion and thickening are the most ‘common clinical presentations. A S8 year old female, non- smoking patient presented to us with dry cough, dyspnoca and left chost pain for several weeks (no asbestas expo- sure) Standard chest X-ray and contrast enhanced multi slice computed tomography revealed a large-size lobulat- ‘od mass originating from the pleura which was diagmosed 2 Department of Pathology, Monaldi Hospital, Naples, 2 Department of Radiology, Momaldi Hoxputa, Naples, Introduction Epithelioid haemangioendothelioma (HE) is a sare malignant vascular tumour of unknown aetiol- ‘ogy with an intermediate aggressiveness between and angiosarcoma. It can arise in ‘organ, but is most often found in the liver and lung. Primary pulmonary EHE. was first described in 1975 by Dail and Leibow and initially termed “in- wavascular bronchioloalveolar tumour (IVBAT)” due to its epithelioid logy and for vascular invasion {1}, Pulmooary EHE. hes & chronic clinical course, the longest surviver being @ ‘female patient who died from pneumonia 24 years after the onset of the disease. In 1993, Kitaichi et al. reported a series of 21 patients affected by pri- mary pulmonary EHE recruited in Asia (2). Mean age at diagnosis or upon the onset of the s ‘was 44 years: males were detected more frequently than females by symptoms, including cough, dysp- snoea and chest pain. Fifteen cases showed bilateral multiple nodular opacities. Partial spontaneous re- gression was demonstrated in three cases. Con- ‘comitance of pleural effusion was associated with a poor prognosis. A further serics of 11 cases of lung as primary pleural haemangioendotheliona (PHE) by his- tology and immunohistockemistry (reactivity for vi- ‘mentin, CD31, CD34, Factor VIIT and ulex exropeas). No metastases were detested. The patieat refused treatment and died three months later due to the onset of acute and progressive respiratory failure. Despite the lack of high- grade malignancy, primary PHE displays a poor progno- sis while curative therapies are actually not available. To cour knowledge this is the first case of primary PEE in a female patient Occurring in Italy and the third one to have literature. Difficulties in diagno ‘management are discussed below. ‘Momalds Arch Chest Dis 2010; 735 3, 135-139, Keywords: Haemangioendothelioma, Immunohistochemistry, Pleura. | Department of Clinical and Experimental Medicine, “Federica University, Noles, 4 Department of Radiology “Magrassi-Lancara”, Second University af Naples, Naples, daly. ‘Correspondence Marialuisa Bocchino, MD, PAD; Department of Clinical and Experimental Medicine, Respiratory Medicine Section, Via S. Pansini 5, 80131 Naples, Italy; e-mails marial ise bocchino@wninait EHEs have been deseribed most recently in Ger- many [3], two cases with different clinical out- comes have been reported in France [4] and two further patients with unusual high resolution CT findings have been described in Japan [5] Unlike the lung EXE primari originating from the Ie pleura (PERS is quile an ur common event. PEHs have been described as iso- lated teports afd small series. All except 2 cases occurred in men aged from 34 to 71 yrs. Pleural fusions and thickening are the most commen cli cal presentations. Despite the lack of high-grade malignancy, PEH is associated with a poor progno- sis resulting in death in the majority of eases while curative therapies are not actually available [6, 7] It usually mimics mesothelioma or adenocarc ma. Distin EHE from epithelioid angiosar- coma is also an issue of concern, Exposure to as bestos and smoking are unproven risk factors. ‘Herein we describe a case of primary PEH oc- curring ina female patient. To our knowledg: is the third to have been made in and the first in Italy. Difficulties in diagnosis and treatment management of primary PEH are dis- cussed.M. BOCCHINO ET AL. Case report A 58-yr old Caucasian female was admitted to the hospital due to dry cough, progressive dysp- noea on exertion and left chest pain for se weeks. The patient referred to have been treated with inhaled bronchodilators with no benefit. Past medical history was significant for epilepsy since the age of 15 year currently under daily treatment with carbamazepine. She kad no history of smok- ing or of occupational exposure to asbestos. Phys- ical examination revealed a significantly decreased expansion of the left hemithorax which was asso- ciated with dullness on percussion and hypoventi lation. Analysis of arterial blood gases was within the normal range when the patient was breathing, ambient air at rest. Oxygen desaturation was in- stead revealed on exercise. Spirometry was not performed as the patient was not compliant. Rou- tine laboratory findings were unremarkable. A. standard chest X-ray showed an extensive mixed opacity in the upper and middle sides of the left hemithorax with associated areas of pleural thick- ening (ligure 1A). A multidetector computed to- mography scan of the thorax showed a moderately sized pleural effusion on the left upper side. There was also pleural thickening which became a nodu- Jar mass up to 12 em in greatest dimension which showed a focally imegular enhancement after the intravenous injection of iodated contrast medium igure 1B). The whole picture was associated with significant left lung volume loss and passive at- eleciasis. All these findings were further analysed in more detail by means of a multiplanar recon- struction (MPR) ¢o- ronal view, as shown in figure 1C. ‘To date, no pul- moni chy- mal nodiles, ade nopaties or pericar- dial effusion were seen to be suggest- ing the disease to be confined to the pleura, Brain and abdominal/pelvis CT scans showed no lesions in other sites and scintigra phy excluded any bone involvement. No. endobronchial lesions were de- tected by means of bronchoscopy. The thoracentesis reve- aled a sero-sangui- neous exudative ef- fusion. Cytological pleural fluid sho- wed 2 high cellular- ity with no evi- dence of malignant m7 Cc) } A cells, A left video-assisted thoracoscopy for pleur- al biopsies was performed. Macroscopic evalua tion revealed the presence of small firm nodules on the parietal pleura while the visceral one and the Jung parenchyma were normal. Light microscoy ‘Sauisaston Sf he pleural rumour thawed fragments of dense fibrosis tissue with infiltration of mononuclear cells and fragments of soft and ‘well vascularised fibrosis. The tumour displayed 2 myzxoid/chondromyxoi ised in 2 nodular pattern and infiltrated by short strands or solid nests of medium-small size tumour cells. The majority of these cells had polarised cytoplasm, in many instances with erythrocytes-containing in- tracellular vacuoles, and bland and clear nuclei with small nucleoli (figure 2A-2B). No necrosis and a very low mitotic activity (<1/10 HPF) were observed (figure 2C). Additional and searce mult- inucleaied cells ing as histiocytoid cells ‘were also present. ‘Tumour cells showed immune- reactivity for vimentin (figure 2D) while stainings for calretinin and cytokeratins 5/6 were negative (figure 2E-2F), Staining for thyroid transcription factor 1, and oestrogen and progesterone receptors were also negative (data net shown). Conversely, tumour cells showed immune-reactivity for CD31, CD34, factor VIII and ulex ewopeaus (figure 3A 3D). A diagnosis highly suggestive of unilateral primary PEH was made on the basis of the radi- ographic, histological and immune-histochemical findings. The patient refused any treatment and left the hospital: she died in her own home three months later due to the onset of acute and progres: sive respiratory failure.PLEURAL HAEMANGIOENDOTHELIOMA IN FEMALE PATIENT Fig. 2.- Parva pleura specimen showing vinous ewes ad nour el ffbiaion (A, Hsemaonglin aad egsin staining. 10X). Higher magnification demonstates that neoplastic cells had delinstaedinza {yloplasnic varuoies f clear eyioplasm. Some tmor ells form raimentary channel, afew of which con thin eryhrucyex (aston) (B. GOX). Evidence of a wingers figure (arom) in (G0X). trumune-hise ‘ining Shows dlfase postive reaciiyy wilh wimenia (D, 40%} and mepauve restviy with eae (E, 20K) and eytakeraine $06 (F, 20) ‘cuining shows posiive wearvisy withthe vascular markers CD31 (A, 60%), CDR {00X) and er europactee(D, 402), A) Fig 1 Immune hiso-caining shows postive eacvily with the vaselar nrkers CD31 (A, 40%), CD34 (8, 40, facuo VI Discussion We have described the case of a unilaterally: localized primary PEF. oceurring in a female patient." Unlike pul- monary EHE which is a relatively good progno- sis tumour most often affecting asymptomatic young and middle-aged women, PEH is a rare and much more aggres- sive disease condition most commonly affect- ing symptomatic older men [6-9]. In. 1999, Pinet et al. described the first case of PEH with peritoneal extension oc- curring in a 50-yr-old fe- male patient in France {10}. ‘That case was characterised firstly by a rapid and aggressive preston an second: by a high chemosen- sitivity with complete response to carbop! and etoposide for at least 18 months from the di- agnosis. More recently, Lee et al. have reported. a further case of PEH extending to the bone and skin in a 31-yrold woman in Korea’ (11). The patient was first submitted to palliative radiotherapy and then started on chemotheray with adriamycin which was switched to mesna- doxorubicin-ifosfamide- dacarbazine duc to the disease progression, reaching an overall sur: vival of 10 months. Generally, prognosis af EHE is quite. variable depending on the site of origin and cannot be predicted on the basis of the clinical and histo- pathologie grounds. Poor prognostic indicators are symptoms ot/and pier. sion at presenta: tion, hepatic metastases, lymphangitic spread, pe- ripheral Iymphadenopa- thy, and the presence of spindle cells in the tumour. As a2 conse-M. BOCCHINO ET AL. quence, differentiation of PEH from the pul- monary counterpart is an issue of concern as prog- nosis and tweatient are different. Differentation from mesothelioma is also important due to clini. cal and radiographic similarities. Additional con- ditions that have to be taken into consideration are the most common presentation of metastatic ade- nocarcinoma and the extremely rare occurrence of primary pleural epitheliod angiosarcoma. Diagno- sis of EHE is on histology and con- firmed by immunohistochemistry, presen- tation on radiology (that is, pleural effusion and thickening) may be highly overlapping. EHE is characterted by short strands and sekd nests of tu: mour cells in a hyaline or myxoid stroma, Well- formed small vessels and multiple intracellular vacuoles are: also present. An reac+ tion may be seen occasionally, A “thabdoid” phe- has also been described [12]. Positive stains with anti-vimentin, anti-CD3UCD34 and anti-Factor VIIVBNH9 antibodies highly indicate the vascular nature of the tumour. To date, the an- titaetor, VUW/ENH stains identity, respectively bighly clffeentisted and undifferenited tumour cells of endothelial origin, Conversely, negativity of anti-c ins staining excludes tumours of spiel onan despite a weak. positivity bas been ‘to oceur also in EHE [13]. A low mi- ic index and the lack of intracellular mucin-con- taining vacuoles are also helpful discriminating features. Further negativity for the mesenchimal differentiation marker, calretinin, excludes mesothelioma. Lastly, distinguishing PEH from josarcoma is instead much more spalercoma i tea mh os, haening overlaps because of their comman derivation [12]. “The distinction of PHE from epitheliod angiosar- ‘coma has not been welll addressed in previous re- However, higher nuclear} ratios, Epica nuclear Dee highly Tokmorphic ep. ‘theliod cells with abundant red cells containing ‘vacuoles and necrosis are more suggestive for the latter, Additional conditions to be considered are the primary fibrous tumour and the desmoids tu- mour of the pleura that are however quite rare ‘events. Differential is of PHE by way of Spal and tadielocial fans is surseassed in ‘table 1. In addition, distinctive immune-histo- chemi are reported in table 2. ‘TconCluton, ts cape pot represen the ‘third case of a primary PHE occurring ina middle- aged female patient, whose diagnosis was con. med by immune-histo-chemistry. The patient ‘was symptomatic at ion with a radiologi- ceal picture indicative of pleural thickening and ef- fusion in association with a large-size pleural mass. No adenopathies and metastases were found ‘suggesting that the tumour was localised and like- ly less aggressive than others reported in the liter- ‘ature, Unfortunately, this was not the case as the patient died soon after having refused any treat- ment. In this issue, although in asymptomatic pa- tients no therapy is considered, curative surgical resection is actually the treatment of choice when ficable. Lung transplantation should be consid- Sea patent with ascular agate ty and pleural hemorrhagic effusion [14]. Various ‘chemotherapeutic agents, including alpha-interfer. ‘on and radiation therapy regimens have been used alone of in conjunction with however no demonstrable therapeutic benefit has been de- scribed to date [1, 2, 9, 10]. Despite this being a ‘Table 1. - Clinieal and radinlogicat differential diagnose of EME im _esma rae Amery Phar enthdom: Adensarzona Mirustimt——tonor aa ‘of thepleara ofthe pleura Sapeinine i F w w Mo Wiaignerasecs) ao oe ee ee iecmepae eee “ : : : Clinical ‘dyspanea, cough, asymptomatic asymptomatic, chest pain chest pain “asymptomatic chest pain, ‘presentation chest pain chest pain ‘dyspnoca and cough —dyspoeea: ‘X-ray ksion ‘moultipls nodular muleiple nodular sltsfori mobifocal focal focal focal ‘appearance ‘plagues plaques and diffese and diffuse lesion a Sartaicn ight pema) (ess tape asad isin = = = » 5 a ‘Pleural thickening ‘frequent infrequent yes we ‘pleural effusion ™ 20 tution Mest = = ne ye i@handdiexs) ys » nePLEURAL HAEMANGIOENDOTHELIOMA IN FEMALE PATIENT ‘Table 2. - Differential diagnosis of EHE by immune-histo-chemistry Primary fibrous Desmoid tumor Epitheliod EH Mesothelioma Adenocarcinoma tumor of the pleura angiosareoma othe pleura CD31+,CD3d+, CD31+,CDH+, ——Calretinine, CKs,TTF-l+, CD344, CD99, Vimentine, smooth ‘Factor VIN, Factor WIIIs, wimentins, CK SiGe, Kisre Bol-2s,EMAs, muscle actins, CKer- CK WTl+ vimentin desmin+, Kio? + KigT 448 KisT is Kis 4f- s100- Ki67- limitation of this report as no information on ther apy response can be provided, we believe that re- porting new cases of rare disease conditions are of, interest for the scientific community as they pro- vide evidence for improving their management in clinical practice. 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