Mediastinal EpithelioidHemangioendotheliomaMetastatic to Lymph Nodesand Pleural Fluid:Report of a CaseTatjana Antic, M.D. and Gregg Staerkel, M.D.*

Epithelioid hemangioendothelioma is a rare mesenchymal tumorof vascular origin, classified as a sarcoma of intermediatemalignant potential. Involvement of numerous sites of the body,including visceral organs, soft tissue, testis, skeleton, brain,meninges, and skin have been described. We report an unusualcase of a mediastinal epithelioid hemangioendothelioma in a 65-year-old female initially presenting as a metastasis to lymphnodes of the hilar region and subsequently as a malignant pleu-ral effusion. The patient had a complex history of papillary re-nal cell carcinoma, papillary thyroid carcinoma, and Walden-strom’s hyperglobulinemia making the diagnosis of metastaticepithelioid hemangioendothelioma difficult. Clinical, cytologicaland immunohistochemical features of this tumor are describedwith an emphasis on diagnostic pitfalls. Diagn. Cytopathol.2010;38:113–116. ' 2009 Wiley-Liss, Inc.

Key Words: epithelioid hemangioendothelioma; metastatic;lymph node; pleural fluid

Epithelioid hemangioendothelioma (EH) is a rare mesen-

chymal tumor of vascular origin designated as a sarcoma

of intermediate malignant potential and unpredictable

behavior. Involvement of numerous sites of the body

including visceral organs, soft tissue, testis, skeleton,

brain, meninges, and skin have been described. Pulmo-

nary EH is a well-known entity since it was first

described by Dail and Liebow1; although at that time, the

exact origin of the tumor was not recognized. The medi-

astinum is a less frequent thoracic location. We report an

unusual case of a 65-year-old female with a mediastinal

epithelioid hemangioendothelioma. Her initial clinical pre-

sentation was that of metastasis to lymph nodes of the

hilar region. Subsequent follow-up demonstrated a malig-

nant pleural effusion. The final diagnosis was rendered

solely on the basis of fine-needle aspiration (FNA) biop-

sies of lymph nodes and pleural fluid cytology.

Case Report

This case involved a 65-year-old Caucasian female with a

complicated history which dated back 30 years when she

was initially seen for thyroiditis. In 1983, the patient had

an episode of gastrointestinal bleeding and CT work-up

revealed a soft tissue density in the lesser curvature of the

stomach. A partial gastrectomy was performed and the

reviewed pathology report noted a diffuse, well-differenti-

ated lymphocytic lymphoma (i.e., small lymphocytic lym-

phoma) with no positive nodes. Radiation therapy was

given. The patient did well for 3 years when she pre-

sented with a 1.5-cm thyroid mass. She underwent a left

thyroid lobectomy. Pathology revealed chronic thyroiditis

and an occult, 0.3 cm, papillary carcinoma. Ten years

later, the patient noted a mass of her medial left eyelid.

The mass was biopsied and found to have a lymphocytic

infiltrate consistent with a small lymphocytic lymphoma.

The patient was followed for 2 years. At this time, the

patient was noted to have a mediastinal mass which was

attributed to her known lymphoma. In addition, an IgM

kappa spike was seen in her serum serology. A diagnosis

of Waldenstrom’s macroglobulinemia was rendered for

which she was treated with 2-CdA (2-chlorodeoxadeno-

sine) and prednisone.

Thirteen years later, a renal mass was discovered and

the patient underwent a left-sided radical nephrectomy

which revealed a 2.0-cm papillary renal cell carcinoma,

type 1. During her recovery, she noted persistent pain in

Department of Pathology, The University of Texas M.D. AndersonCancer Center, Houston, Texas

*Correspondence to: Gregg Staerkel, M.D., Department of Pathology,The University of Texas M.D. Anderson Cancer Center, 1515 HolcombeBlvd, Houston, TX 77030. E-mail: gstaerke@mdanderson.org

Received 29 April 2009; Accepted 29 June 2009DOI 10.1002/dc.21162Published online 17 August 2009 in Wiley InterScience (www.

interscience.wiley.com).

' 2009 WILEY-LISS, INC. Diagnostic Cytopathology, Vol 38, No 2 113

the surgical field. She noted weight loss and at times diffi-

culty with breathing. Four months post renal surgery, she

underwent a fiberoptic bronchoscopy with endobronchial

ultrasound and transbronchial FNA biopsy of thoracic

lymph nodes. The cytopathology from level 7 (subcarinal)

and 4R (lower paratracheal) lymph nodes, together with

subsequently acquired pleural fluid cytology, revealed

epithelioid hemangioendothelioma. Shortly thereafter, the

progression of this patient’s disease, together with her

other comorbidities, resulted in her death.

Cytologic Findings

Smears from all three sites mentioned earlier were air-

dried or alcohol-fixed and stained in the usual fashion

with Diff-Quik or Papanicolaou stain, respectively. Cell

blocks were prepared from residual tissue obtained from

needles rinsed into growth media (RPMI) solution.

Hematoxylin and eosin slides and unstained sections for

immunohistochemical studies were acquired from the cell

block preparations. Lymph node smears demonstrated

single cells and small and large loosely cohesive cell

groups of round to polygonal epithelioid cells focally

forming pseudopapillary and pseudoacinar structures in a

background of lymphocytes (Fig. 1). Moderate dense

cytoplasm and mild nuclear pleomorphism were seen.

Nuclei showed inconspicuous nucleoli. No mitotic figures

were found. The specimen from the pleural fluid also

showed loosely cohesive cell groups with pseudopapillary

and pseudoacinar structures. Rare cells within groups had

a signet ring appearance (Fig. 2). Diff-Quik prepared

smears revealed nuclei with intranuclear cytoplasmic

inclusions (Fig. 3). The cell block preparation revealed

numerous cells with a similar signet ring appearance and

rare cytoplasmic lumina containing red blood cells (Fig.

4). Immunohistochemical studies, performed on cell block

sections from all three sites, revealed tumor cells to be

positive for CD31 (Fig. 5a) and CD34 and focally posi-

tive for cytokeratin (Fig. 5b).

Discussion

EH is a rare mesenchymal tumor of vascular origin which

is designated as a sarcoma of intermediate malignant

potential. Involvement of numerous body sites, including

visceral organs, soft tissue, testis, skeleton, brain,

meninges, and skin have been described. Pulmonary EH

is a well known entity which was first described by Dail

and Liebow1 as an intravascular bronchioloalveolar tumor.

The authors thought these tumors were an aggressive

Fig. 1. FNA of thoracic lymph node demonstrating loosely cohesivegroups of round to polygonal epithelioid cells focally forming pseudo-papillary and pseudoacinar structures in a background of lymphocytes(Papanicolaou stain).

Fig. 2. Rare cells from a thoracic lymph node FNA presenting with asignet ring morphology (Papanicolaou stain).

Fig. 3. Malignant cells of EH with a single cell showing an intranuclearcytoplasmic inclusion (Diff-Quik).

ANTIC AND STAERKEL

114 Diagnostic Cytopathology, Vol 38, No 2

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form of bronchioloalveolar carcinoma with a propensity

for vascular invasion. Later, Dail and others2–7 recognized

the vascular nature of EH. In 1982, Weiss and Enzinger8

gave a detailed description of a soft tissue counterpart

and coined the name ‘‘epithelioid hemangioendothe-

lioma’’. Subsequent reports further defined this entity with

two recent reports offering independent predictors of

survival. The clinical symptoms of cough, chest pain,

dyspnea, hemoptysis, and weight loss and the presence of

a pleural effusion were poor outcome predictors.9–11

Pulmonary EHs constitute the majority of thoracic based

EHs. They often present as multifocal tumors affecting

predominantly females.12 Morphologic features of pulmo-

nary EHs, as well as a primary pleural EH with

rhabdoid phenotypes, in cytologic specimens, have been

described.13–15 Metastases to lymph nodes are a rare

event.10 Amin et al.,10 in their review of the literature,

found that of 93 patients with pulmonary EH, 47 (50.5%)

developed metastatic disease of which only 10.8% had

metastasis to lymph nodes. For EHs that arise in the less

frequent thoracic location of the mediastinum, the anterior

compartment is the most common site of involvement.

Only 34 cases of mediastinal EH have been reported with

the largest series published by Suster et al.16 Just one

case has been noted to arise in the posterior mediasti-

num.17 Although pulmonary EH mostly affects females,

such a gender distribution is not found for mediastinal

cases, in fact, there is a slight male predominance.16,17

Clinical prognostic factors for mediastinal EH have not

been studied but one can reasonably conclude that

patients with similar clinical symptoms and distant metas-

tasis as seen with pulmonary EH patients will have a

worse prognosis. Deyrup et al.18 reviewed 51 cases of

soft tissue EH, including four in the mediastinum, trying

to develop histologic criteria on which one could predict

patient outcome. A combination of the tumor’s mitotic

rate and size appear to correlate best. For the 34 cases of

mediastinal EH reported, none were discovered due to

suspected lymph node metastasis or malignant effusion

and none were diagnosed purely on cytology. Our

patient’s diagnosis was complicated by her previous his-

tory of renal cell and thyroid carcinomas. Although multi-

ple and/or synchronous malignancies are an infrequent

occurrence, this possibility emphasizes the importance of

a detailed work-up, including immunohistochemical stud-

ies. It is necessary to take into account the nature of prior

malignancies (i.e., stage, grade, biologic potential, etc.).

In the case of our patient, the fact that her papillary renal

cell carcinoma was type 1, 2.0 cm in size and confined to

the kidney and that her papillary thyroid carcinoma was

Fig. 4. Cell block preparation from pleural fluid revealing additional sig-net ring-like cells and rare cytoplasmic lumina containing red blood cells(arrow) (H&E).

Fig. 5. (a) An immunohistochemical stain performed on a cell blocksection from pleural fluid demonstrating strong positivity for CD31 in tu-mor cells. (b) Additional immunohistochemical stain illustrating weak,focal positivity for pancytokeratin (background mesothelial cells arestrongly positive).

MEDIASTINAL EPITHELIOID HEMANGIOENDOTHELIOMA

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occult and remote, spoke against the possibility of meta-

static disease from these two sites. In addition, it would

be unusual for a kidney or thyroid primary to manifest

with an initial mediastinal metastasis without regional

lymph node, bone and/or lung involvement. Cytomorpho-

logic features [i.e., absence of fibrovascular cores, three-

dimensional cell groups and signet ring-like cells (‘‘blister

cells’’) with or without inscribed red blood cells] in this

case did not suggest papillary renal cell or papillary thy-

roid carcinoma. For tumors with unusual atypical mor-

phology, unusual location or broad differential diagnostic

concerns, immunochemical studies can provide help, if

a panel is performed. The fact that EH can be focally pos-

itive for cytokeratin could be misleading if the immuno-

panel used is limited. Specifically, EH can express keratin

in 25% of cases.19 Markers of vascular differentiation are

most informative, although in rare occasions, one or more

of them are not expressed.16 Of interest in our patient was

the fact that her pleural fluid also contained a malignant

lymphocytic population, consistent with her history of

low grade B-cell lymphoma which was confirmed by flow

cytometry.

In summary, EH is a rare malignant vascular neoplasm

with unpredictable behavior, mimicking either benign or

malignant conditions. Recognition of EH has both clinical

and prognostic implications since, although considered a

malignant neoplasm, it still has a better prognosis than

most carcinomas. In addition, although no therapeutic

modality other than surgery is effective in EH, some

patients can achieve long term survival despite metastatic

disease. Therefore, there is a meaningful role for cytology

to play in providing for an accurate diagnosis in cases of

EH, especially when core needle or excisional biopsy is

not possible due to clinical circumstances. Awareness of

EH and a thorough work-up is key to an accurate

diagnosis.

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