Unusual hemangioendothelioma of the liver with epithelioid morphology associated with marked eosinophilia: Autopsy case

Case Report

Unusual hemangioendothelioma of the liver with epithelioidmorphology associated with marked eosinophilia: Autopsy case

Tokuhiro Kimura,1 Makio Mukai,2 Yuko Kaneko,3 Michito Hirakata,3 Shinichiro Okamoto,3 Michiie Sakamoto,1

Yasunori Okada1 and Yasuo Ikeda3

1Department of Pathology, 2Division of Diagnostic Pathology and 3Department of Internal Medicine, Keio UniversitySchool of Medicine, Tokyo, Japan

Vascular neoplasms characterized by epithelioid endothelialcells consist of several different entities from benignity tohigh-grade malignancy. Because of histological overlapbetween them, there is substantial difficulty in classifyingthem correctly. The present patient, a 33-year-old man,presented with hepatomegaly, striking eosinophilia andelevated serum interleukin-5 level. Biopsy and autopsyrevealed an unusual epithelioid vascular tumor in the liver,which is histologically distinct from epithelioid hemangioma,epithelioid hemangioendothelioma, or epithelioid angiosar-coma. The tumor cells had vasoformative and partly solidgrowth with no severe nuclear atypia and very low mitoticactivity, and the histological features were similar to those ofthe entity recognized as hemangioendothelioma of bone.Organs other than the liver, for example the testes and bone,were also involved. This tumor should be considered in thedifferential diagnosis of severe eosinophilia.

Key words: angiosarcoma, eosinophilia, hemangioendothe-lioma, hemangioma, interleukin-5, liver

Some vascular tumors are characterized by proliferation ofendothelial cells with plump cytoplasm. These cells are fre-quently called epithelioid endothelial cells. Vascular tumorscomposed of epithelioid endothelial cells include severaldifferent entities, the diagnosis of which is sometimes con-fusing. In soft-tissue pathology, epithelioid vascular tumorsare classified as epithelioid hemangioma (EH), epithelioidhemangioendothelioma (EHE), and epithelioid angiosarcoma(EAS).1–3 Practically, considerable overlap is present in thehistological features of these tumors. In bone, vasculartumors with epithelioid morphology include hemangioendo-

thelioma of bone in addition to EH, EHE, and high-gradeangiosarcoma, although there is a controversy.4–7 However,in the liver, so far, EHE and EAS are known as epithelioidvascular neoplasms.8 Here we report a case of an unusualepithelioid vascular tumor, the histological phenotype ofwhich was distinct from EH, EHE or EAS, but was similar tohemangioendothelioma of bone. The tumor affected the liverand, to a lesser extent, other various organs, and character-istically the patient had striking eosinophilia.

CLINICAL SUMMARY

A 33-year-old man was admitted to hospital because of facialflushing and palpitation after eating. He also complained ofmild fever, nausea and eruption on his extremities and trunk.His family history was unremarkable. He denied substance/alcohol abuse or professional hazard exposure. He hadpollen allergy but no history of asthma.

Physical examination revealed hepatosplenomegaly anditchy eczematous skin lesions scattered on the extremitiesand trunk. A CT scan of the abdomen demonstrated multiplelesions of various densities in both lobes of his swollen liver(Fig. 1a). Laboratory findings were remarkable for strikingeosinophilia of the peripheral blood (white blood cell count,44 100/mL; absolute eosinophil count, 39 000/mL). Serumlevels of IgE (96 400 IU/mL; reference range, �600 IU/mL),and interleukin-5 (IL-5; 164 pg/mL; reference range, �10 pg/mL) were elevated. Serological tests for syphilis, humanimmunodeficiency virus and helminthic parasites were nega-tive. A bone marrow biopsy showed hypercellular marrowwith increased eosinophils (immature and mature) andmegakaryocytes, but significant neoplastic changes were notidentified. Neither chromosomal abnormality nor the fusiongene bcr-abl was detected in the bone marrow cells. A skinbiopsy from the eczematous lesions showed a perivascularand perifollicular inflammatory infiltrate of eosinophils andlymphocytes. Cutaneous hemangioma was not found.

Correspondence: Makio Mukai, MD, Division of Diagnostic Pathol-ogy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]

Received 2 April 2006. Accepted for publication 18 July 2006.© 2006 The AuthorsJournal compilation © 2006 Japanese Society of Pathology

Pathology International 2006; 56: 694–701 doi:10.1111/j.1440-1827.2006.02032.x

mailto:[email protected]

A needle biopsy of the liver demonstrated marked eosi-nophil infiltration and vascular proliferation characterized bywell-formed blood vessels lined with plump endothelial cellswith eosinophilic cytoplasm and a large vesicular nucleuswith a central nucleolus (Fig. 1b,c). Intracytoplasmic vacu-oles were occasionally found in these plump cells. Immuno-histochemically (antibodies used are listed in Table 1), theseplump cells were positive for CD31 and von Willebrandfactor. They were negative for CD34 and cytokeratin AE1/AE3. No mitotic figures were found, and no Ki-67/MIB-1-positive nucleus was noted in these plump cells. Noevidence of parasitic infection, granuloma or vasculitis wasidentified.

Steroid therapy (prednisolone, 60 mg/day) was initiated inan attempt to control eosinophilia, but peripheral blood eosi-nophils were not decreased sufficiently (absolute eosinophilcount, 9000/mL). The skin lesions and edema were improved.His serum IL-5 level dropped to 38.5 pg/mL, although thiswas higher than the normal limit. In addition to prednisolone,the patient was started on hydroxyurea (2 g/day) but it washalted because of drug-induced thrombocytopenia, and thuscyclosporin (250 mg/day) was used instead. Due to thesetherapies, peripheral blood eosinophil counts were success-fully controlled to the level of 1000/mL. During the courseof these therapies, the second liver biopsy was performed.Consistent with the controlled eosinophil counts, the biopsy

a b

c d

Figure 1 (a) Contrast-enhanced computed tomography scan of the abdomen. Multiple lesions of various densities are seen in both lobes ofthe liver. (b) Low-power view of the first biopsy of the liver (before therapy) showing vascular proliferation with a prominent inflammatoryinfiltrate. Arrowhead, intrahepatic bile duct. (c) High-power view of (b). Marked eosinophil infiltration and proliferation of well-formed bloodvessels lined by plump endothelial cells are observed. Arrow, intracytoplasmic vacuole. (d) Second biopsy of the liver (after therapy with steroidand hydroxyurea). No eosinophil infiltration is found, but the vascular tumor remains.

Unusual hemangioendothelioma of liver 695

© 2006 The AuthorsJournal compilation © 2006 Japanese Society of Pathology

showed no eosinophil infiltration but the vascular tumorremained (Fig. 1d). Among the initial symptoms, nausea,which shifted to loss of appetite, and facial flushing were notsignificantly ameliorated.

Approximately 1 year after the initial admission, weightloss and jaundice developed, and his level of consciousnessbegan to be impaired, although his peripheral eosinophilcounts were well controlled. His liver function continued todeteriorate, and the patient died due to liver failure andaspiration pneumonia.

AUTOPSY FINDINGS

Liver

Grossly, the liver showed marked hepatomegaly (4160 g)and ill-defined multiple spongy lesions were scatteredthroughout (Fig. 2a). Nodular gray to white areas, 2–6 cm indiameter, were observed (Fig. 2a), which corresponded tothe low-density areas in the CT scan (Fig. 1a).

Microscopically, the lesions were composed of proliferationof well-formed blood vessels lined by epithelioid cells withabundant eosinophilic cytoplasm and a large vesicularnucleus with a central nucleolus (Fig. 2b,c). Nuclei of thesecells were round or lobulated. Most of these tumor cellsformed vascular spaces of various sizes, many of which weredilated. Focal solid-growth areas with few vascular spacesbeing formed were also observed, and comprised �5% of thetumor area (Fig. 2b(upper left),d). The tumor cells with vacu-olated cytoplasm were present (10–20% of the tumor cells;Fig. 2c,d). The tumor replaced sinusoids, and lesional livercell plates tended to become atrophic (Fig. 2c). The tumorcells often infiltrated terminal hepatic venules. Fibrous oblit-eration of terminal hepatic venules was also seen. Replace-ment of the endothelia of middle-sized hepatic vein branchesby the tumor cells was sometimes observed. In portal tracts,the tumor cells occasionally invaded portal vein branches,but arterial involvement was rarely seen.

Areas showing spongy appearance at macroscopic exami-nation exhibited dilated and congested vascular spaces remi-niscent of cavernous hemangioma, but the spaces were linedby the plump epithelioid cells rather than flattened endothelialcells (Fig. 2e). Nodular gray to white areas seen on grossexamination were found to be foci of hyalinization.

Immunohistochemistry demonstrated that these plump epi-thelioid cells, whether in a vasoformative area or in a solid-growth area, were positive for CD31 (Fig. 2f), and weaklypositive for von Willebrand factor. They were negative forCD34 (Fig. 2g), glucose transporter type 1 (GLUT1), andcytokeratin AE1/AE3. Mitotic figures were very rare (�1 per50 high-power fields), and no atypical mitotic figure wasseen. The number of Ki-67/MIB-1-positive cells was verysmall (�0.5%).

Immunostaining using anti-IL-5 antibody was performed onthe biopsy and autopsy specimen. The first biopsy specimenhad a granular cytoplasmic staining pattern in the tumor cellsas well as eosinophils (Fig. 3a). In the second biopsy andautopsy, the tumor cells showed positive staining, but thestaining intensity was relatively weak compared with the firstbiopsy (Fig. 3b).

No microorganism was found in the lesions by Warthin-Starry stain.

Other organs

Small tumors, which were �5 mm in diameter and his-tologically similar to the liver tumor, were found in thespleen, testes, mesenteric artery, vertebrae, lungs, heart(papillary muscles and coronary arteries), and lymph nodes(abdominal–paraaortic and paratracheal). The bilateraltestes showed arteriovenous malformation (AVM; Fig. 4a).Bilateral testicular arteries and blood vessels in the AVM hadirregular intimal thickening, and the endothelial cells of thesevessels focally demonstrated epithelioid morphology; foci ofpapillary proliferation were also observed (Fig. 4a,b). Similarfoci of epithelioid endothelial cell proliferation accompaniedby irregular intimal thickening were found in the mesentericartery. In the bone, small tumors were present in the bodies

Table 1 Antibodies used

Anti- Antibody clone Dilution Antigen retrieval Source

CD31 JC/70A 1:100 Proteinase K Dako, Glostrup, Denmarkvon Willebrand factor Polyclonal 1:1000 Proteinase K Dako, Glostrup, DenmarkCD34 QBEnd/10 1:100 Heat (citrate buffer) Novocastra, Newcastle upon Tyne, UKCytokeratin AE1/AE3 1:200 Heat (citrate buffer) Dako, Glostrup, DenmarkKi-67 MIB-1 1:100 Heat (citrate buffer) Dako, Glostrup, DenmarkIL-5 9906.1 1:1500 – G-T, Minneapolis, MN, USAGLUT1 Polyclonal 1:1000 Heat (citrate buffer) Chemicon, Temecula, CA, USA

GLUT, glucose transporter; IL, interleukin.Formalin-fixed, paraffin-embedded tissue sections were stained with antibodies listed here using Histofine Simple Stain kit (Nichirei Biosciences,

Tokyo, Japan) or Envision+ kit (Dako). Diaminobenzidine was used as a chromogen, and the sections were counterstained with hematoxylin.

696 T. Kimura et al.


of the third, fourth, sixth and seventh thoracic vertebrae(Fig. 4c). In the lymph nodes, small tumors were present incontinuity with the fibrous tissue of the capsule or trabecula.

No vascular tumor was found in the skin or soft tissues.Eosinophil infiltration was not seen in the skin or viscera atautopsy.

DISCUSSION

Epithelioid vascular tumors consist of several different enti-ties from benignity to high-grade malignancy. EH (previouslycalled angiolymphoid hyperplasia with eosinophilia) is abenign tumor characterized by well-formed vessels lined byepithelioid endothelial cells with a large nucleus with an openchromatin pattern.1 EHE is a malignant neoplasm, and iscomposed of cords and nests of epithelioid cells in a char-acteristic myxohyaline stroma. These cells only rarely formwell-defined vascular channels.1–3,8 EAS is a high-grademalignant tumor composed predominantly of epithelioid cellswith a large vesicular nucleus, showing pleomorphism andhyperchromatism. Tumor cells of EAS form vascular chan-nels or grow in solid pattern.1–3,8 In contrast, in the field ofbone tumor pathology, tumors named ‘hemangioendothe-lioma of bone’ are recognized as neoplastic proliferations ofepithelioid endothelial cells with no severe atypia, andshowing vasoformative and solid growth.4,6

CD31, CD34 and von Willebrand factor are commonlyused endothelial markers. Immunohistochemical studies ofthe present case showed that the tumor cells, both in thevasoformative area and in the solid-growth area, were posi-tive for CD31 and von Willebrand factor, confirming endothe-lial differentiation.

The histological features of the present tumors are sounusual that it is inappropriate to classify them as EH, EHE,or EAS. The first biopsy of the liver showed well-formedvessels lined by epithelioid endothelial cells with an eosino-philic infiltrate. This microscopic finding closely resembledthat of EH. However, autopsy demonstrated an epithelioidvascular tumor infiltrating along hepatic sinusoids, terminalhepatic venules and occasionally portal vein branches, whichwas inconsistent with a benign process. The tumors werepredominantly composed of well-formed vascular channels,and solid clusters of cells such as those in Fig. 2(d) were onlyfocal findings, indicating that they were different from EHE.Myxohyaline stroma, which is characteristic of EHE, was notpresent in the current case. Next we considered the possi-bility of EAS. Nuclei of the tumor cells of the present caseshowed no severe atypia, no hyperchromatism, and no sig-nificant pleomorphism. Mitotic activity was very low, and sowas the Ki-67 labeling index. This is in contrast with angio-sarcoma, which commonly has a high Ki-67 labeling index.9

Foci of spindle cell proliferation or extramedullary hemato-

poiesis were absent. These features were incompatible withhepatic EAS, although the possibility of ‘exceptionally blandangiosarcoma’ is not completely excluded. Many tissueblocks were sampled from the liver at autopsy, but a focus ofsufficient atypia to facilitate a diagnosis of EAS was notfound. In addition, GLUT1, characteristically expressed ininfantile hemangioendothelioma of the liver,10 was negative inthe present case.

Although the organ is different, we noticed a striking simi-larity between the present tumors and the entity ‘heman-gioendothelioma of bone’. The histological features of theentity and the differential diagnosis from angiosarcoma arebest summarized by Evans et al.: (i) tumor cells of heman-gioendothelioma of bone have growth patterns ranging fromvasoformative to solid, but well-formed vessels are constantfindings; (ii) the cells have epithelioid morphology, and intra-cytoplasmic vacuoles are sometimes present; (iii) nuclearhyperchromatism and polymorphism are not more thanslight; (iv) mitotic rate is generally low; and (v) variousdegrees of eosinophil infiltration are sometimes seen.4

Follow-up data by Evans et al. indicate that hemangioendot-helioma of bone is a low-grade malignant, occasionallymetastasizing neoplasm.4 Therefore we propose that thepresent liver tumor should represent a new type of heman-gioendothelioma of liver that resembles hemangioendothe-lioma of bone and is distinct from EHE and angiosarcomahistologically.

In the present case, small tumors of similar histology to theliver tumor were found in many organs. They were highlysuggestive of metastatic lesions. However, one of theremarkable findings in the present case was the associationof AVM and epithelioid vascular tumor in the bilateral testes.The mesenteric artery also exhibited intimal thickening andepithelioid cell proliferation. Therefore it cannot be deniedthat the tumors of various organs in the present case weredeveloped multifocally on the certain underlying abnormalityin the vascular system. With regard to EHE, multiorganinvolvement of lung, liver, bone, and other sites is well known,but whether it is the result of metastasis or multifocality is notfully understood.

There are several reported cases of adult-onset heman-giomas arising in multiple visceral organs (such as the liver,spleen, bone marrow, lung, or ovary).11–13 They are calledsystemic hemangiomatosis, and considered to be a hamar-tomatous disease11,13 or a process that is developed on thebasis of a certain systemic endothelial abnormality.12 If themultiple tumors of the present case are of multicentric origin,it may be possible to regard the present case as a sort ofhemangiomatosis, but the reported cases of systemichemangiomatosis usually consist of cavernous or capillaryhemangioma, and none of these cases demonstrated defi-nite epithelioid morphology. In contrast, the entity ‘angioma-tosis’ is a diffuse form of hemangioma affecting a large



a

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d e f

g



segment of the body, for example the limb.1–3 The presentcase was different from angiomatosis in the sites of involve-ment and histological features.

Marked eosinophilia was observed in the present case.Among many factors involved in eosinophilopoiesis, IL-5 isknown to be a major cytokine that plays essential roles in theproduction and activation of eosinophils.14,15 IL-5 is reportedto be produced by T lymphocytes, mast cells, eosinophils,16

and progenitor cells for eosinophils.17 Evidence of IL-5 over-production has been described in various diseases showingeosinophilia.18,19 In the present case, the serum IL-5 levelwas elevated, and the tumor cells as well as eosinophilsinfiltrating the tumor tissue were immunoreactive for IL-5.These findings suggest the possibility that IL-5 production bythe tumor cells (and eosinophils) triggered eosinophilia in thepresent patient.

After steroid therapy, the serum IL-5 level was lowered. Wespeculate that this decrease resulted from suppression ofIL-5 production by immune cells (eosinophils, their progenitorcells, and lymphocytes), because previous experimentalstudies showed that corticosteroids inhibited IL-5 productionby lymphocytes20,21 and eosinophil progenitors.17 Howeverthe IL-5 level after steroid treatment was higher than normal,suggesting that the tumor cells (as well as residual eosinophillineage cells) continued to secrete IL-5. IL-5 immunoreactiv-ity of the tumor cells remained positive at the second biopsyand autopsy, although the intensity of the immunostainingbecame relatively weak after the therapy. This indicates that

prednisolone and cyclosporin had a limited inhibitory effecton IL-5 production by the tumor cells.

This patient had various symptoms including nausea, facialflushing, skin lesions and edema. The mechanisms of thesephenomena were unknown, but the skin lesions and edemawere improved after steroid therapy, implying that these twosymptoms were caused by the striking excess of eosinophilsor IL-5. In contrast, facial flushing and nausea, whichremained throughout the course, were possibly related to theliver tumor itself.

Treatment for this vascular tumor is unknown. In this case,steroid, hydroxyurea and cyclosporin were used in order tocontrol eosinophilia, rather than to target tumor cells,because pathological findings of the liver biopsies were sounusual that conclusive biopsy diagnosis was unachievable.Peripheral blood eosinophilia was successfully controlleddue to these therapies, but the tumor size did not respondand liver failure followed. If the liver tumor of this patient hadbeen localized and of a resectable size at initial presentation,liver failure due to the replacement of his liver by the tumorwould have been avoided by surgical resection. Liver trans-plantation might be a choice, as in treatment for EHE.22 Therole of chemotherapy would be unclear because it is not veryeffective in EHE.22

In conclusion, we have described an unusual type ofhemangioendothelioma of the liver, the histology of whichclosely resembles that of hemangioendothelioma of bone.Marked eosinophilia, possibly mediated by IL-5, occurred

Figure 2 Autopsy findings of the liver. (a) On gross examination, spongy lesions are scattered throughout the swollen liver, and nodular grayto white areas are also found. (b,c) Microscopic examination reveals proliferation of well-formed blood vessels lined by plump endothelial cells(arrowheads, atrophied liver cell plates). (b,d) Focally, solid growth of these plump cells is observed. (e) Cavernous hemangioma-like dilatedvascular spaces are also found, which are lined by the plump endothelial cells (e, inset). Immunohistochemically, the plump cells are (f) positivefor CD31 but (g) negative for CD34.

�

a b

Figure 3 Immunostaining for inter-leukin-5 in the liver tumor tissue. (a)The first liver biopsy specimen exhibitsgranular cytoplasmic staining in thetumor cells (arrows) and eosinophils(asterisks). (b) At autopsy, the tumorcells show positive staining, but thestaining intensity is relatively weakerthan in (a).



and intensive therapy was required to control it. This tumorshould be included in the differential diagnosis of hypereosi-nophilic syndrome, and careful interpretation of both biopsyfindings and imaging studies is important. Particularly,pathologists should keep in mind the deceptively blandappearance of the first liver biopsy of the present case.Because the tumor had already affected the liver extensivelyat the time of the initial admission, the course of progressionis still unclear. To clarify the biological behavior of the tumorof this type, accumulation of cases like this is necessary.

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Figure 4 Autopsy findings of the testis and bone. (a) There isarteriovenous malformation (AVM) in the testis. (b) High-power viewof (a). Papillary proliferation of plump endothelial cells are observedin the vessels of the testicular AVM. Arrowheads, atrophic seminif-erous tubules. (c) Vasoformative growth of plump endothelial cells isfound in the thoracic vertebra.



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Unusual hemangioendothelioma of the liver with epithelioid morphology associated with marked eosinophilia: Autopsy case