Case 1 -
Pleural Epithelioid Hemangioendothelioma
Samuel A. Yousem
University of Pittsburgh Medical Center
Click on each slide thumbnail image for an enlarged view
43-year-old woman with pleuritic chest pain
associated with a hemorrhagic pleural effusion, who was found on CT scan to have a pleural based mass
with associated diffuse pleural thickening. A pleural biopsy was performed.
Case 1 - Slide 1
Case 1 - Figure 1
A cellular process thickens the visceral pleura and expands and extends down interlobular septa.
Case 1 - Figure 2
The thickened pleura has a vague nodularity with increased cellularity in these zones.
Case 1 - Figure 3
Focally, myxomatous change is observed in the pleural "plaque".
Case 1 - Figure 4
The cellular infiltrate is paucivascular with a whirling storiform architecture.
Case 1 - Figure 5
At the pulmonary parenchymal and visceral pleural interface, focal necrosis is observed and air spaces are filled by a dyscohesive cellular infiltrate.
Case 1 - Figure 6
The cellular infiltrate consists of mildly pleomorphic epithelioid and spindle cells that spill into air spaces and cuff small blood vessels.
Case 1 - Figure 7
Cytologically, the epithelioid cells have round to oval nuclei, diffuse chromatin, and abundant glassy eosinophilic cytoplasm.
Case 1 - Figure 8
Occasional cells have cytoplasmic vacuoles which indent their nuclei.
Case 1 - Figure 9
The spindle cells have similar cytologic qualities to the epithelioid elements.
Pleural epithelioid hemangioendothelioma.
Epithelioid hemanagioendothelioma is a low grade
sclerosing angiosarcoma which was initially reported as an intravascular bronchioalveolar tumor (IVBAT).
While best described in the lung, epithelioid hemangioendotheliomas (EHE) have been reported in the bone,
soft tissue, liver, and other sites.
Primary pulmonary epithelioid hemangioendothelioma has a marked predilection for young white women
(F/M = 4) commonly occurring in individuals under the age of 50 years. Approximately 50% of patients are
asymptomatic, while the remainder present with non-specific complaints of dyspnea, cough and chest pain.
Chest radiographs and high resolution CT scans show multiple bilateral small nodules, usually less than 2
cm in diameter, often localized to the vasculature of the lung. Rarely these nodules will be calcified.
The overall appearance strongly suggests metastatic disease. When surgically resected, the nodules are
ill-defined, grayish-white and non-encapsulated and often have a cartilaginous or myxomatous quality. In
many instances, central yellow necrosis is identified.
The histopathology of EHE has been best described in its pulmonary parenchymal manifestation. These
lesions typically form well-circumscribed nodules, with a central region of coagulative eosinophilic
necrosis and a periphery characterized by myxohyaline micropolyps filling air spaces, and permeating the
pores of Kohn. At the periphery, the air spaces are filled with a variably hyalinized, mucinous, myxoid,
and even chondroid ground substance, lined by reactive alveolar pneumocytes at their advancing edge.
Within the ground substance are numerous bland polygonal cells. These cells have round to oval nuclei,
diffuse fine chromatin, inconspicuous nucleoli, and moderate to abundant amounts of glassy eosinophilic
cytoplasm. The nuclei may contain intranuclear inclusions and can be grooved, and the cytoplasm contains
small vacuoles that suggest signet ring differentiation. In some instances, the vacuoles contain red
blood cells. These tumors have a propensity to infiltrate the vasculature of the lung, particularly the
veins, and often form intraluminal polypoid plugs within the lumen of small bronchioles. Cytologic
studies on EHE show that the neoplastic cells form clusters around central hyaline cores, giving a
papillary or "ship's wheel" configuration. Cytoplasm is glassy, eosinophilic, and may have a rhabdoid
appearance. Immunoperoxidase stains demonstrate that the proliferating cells express Factor 8, Ulex
europaeus, CD31, and CD34 reflecting their endothelial differentiation. S100 protein may be expressed in
approximately 15% of cases, and stains for estrogen receptor are positive in 20% of cases. Stains for
progesterone receptor are negative. In up to 20% of cases, immunostains for low molecular weight
cytokeratin are positive. If ultrastructural studies are performed, these cells may contain the
cytoplasmic Weibel Palade bodies that are characteristic of endothelial tumors.
While the above description highlights the classic morphology of EHE in the lung, it should be noted
that there are clinicopathologic variants that need to be recognized. This case specifically emphasizes
a presentation of EHE that mimics mesothelioma in manifesting as diffuse pleural disease. Other cases of
EHE may manifest as solitary, often calcified, nodules, lymphangitic tumor with expansion of the
interlobular septa; thromboembolic disease, or in some instances as a mediastinal mass with diffuse
The behavior of EHE often is reported as "good" with a 70% five year survival. Patients with
pulmonary EHE often have metastases to the pleura, liver and bone. While this survival rate represents
an overall figure, there are two distinct clinical groups that have vastly different prognoses. Those
patients who present in an asymptomatic fashion with multiple pulmonary parenchymal nodules may have a
very long survival, in most instances over 15 years. A separate subgroup, however, does present with a
much more aggressive clinic course. These patients are typically men who present with evidence of
extensive vascular and pleural invasion, in that the patients present with alveolar hemorrhage with
hemoptysis, hemorrhagic pleural effusions, and anemia, and have a much more rapid progressive downhill
clinical course. Although only approximately 150 tumors have been reported in the literature, poor
prognosis overall seems to relate to the following features: male sex, symptomatic presentation,
hemoptysis, multiple nodules, pleural effusion, extensive intravascular growth, metastases to lymph
nodes, and spindle cell growth.
From a differential diagnostic prospective, the major considerations relate both to the morphologic
appearance and to the clinical presentation. This case highlights both a clinical presentation
resembling malignant mesothelioma, as well as the morphologic resemblance of EHE to mesothelial
neoplasms. Angiosarcoma of lung tends to present with higher grade cytology and forms interanastomosing
vascular channels, that precipitate a clinical presentation with hemoptysis and alveolar hemorrhage.
Metastatic carcinoma can be confused with EHE, specifically signet ring variants, and cytokeratin stains
in the setting of negative endothelial markers can be a helpful feature. Cartilaginous tumors have been
included in the differential diagnosis in the past, however they are rarely confused currently. Reactive
conditions including organizing pneumonia must also be considered with the key discriminator being the
recognition of the independent proliferation of cytologically bland endothelial cells.
- Amin RM, Hiroshima K, Kokubo T, et al. Risk factors and independent predictors of survival in patients with pulmonary epithelioid haemangioendothelioma. Review of the literature and a case report. Respirology. 2006, 11:818-825.
- Bagan P, Hassan M, Le Pimpec Barthes F, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: a review of the literature. Annals of Thoracic Surgery. 2006, 82:2010-2013.
- Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature.[see comment]. Chest. 2004, 125:789-793.
- Dail DH, Liebow AA, Gmelich JT, et al. Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT). An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer. 1983, 51:452-464.
- Hristova EN, Krishnamurthy S, Ro JY, et al. Pulmonary epithelioid hemangioendothelioma with prominent signet ring cell features mimicking metastatic adenocarcinoma. Annals of Diagnostic Pathology. 2003, 7:160-164.
- Kitaichi M, Nagai S, Nishimura K, et al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. European Respiratory Journal. 1998, 12:89-96.
- Saqi A, Nisbet L, Gagneja P, et al. Primary pleural epithelioid hemangioendothelioma with rhabdoid phenotype: report and review of the literature. Diagnostic Cytopathology. 2007, 35:203-208.
- van Kasteren ME, van der Wurff AA, Palmen FM, et al. Epithelioid haemangioendothelioma of the lung: clinical and pathological pitfalls. European Respiratory Journal. 1995, 8:1616-1619.
- Yousem SA, Hochholzer L. Unusual thoracic manifestations of epithelioid hemangioendothelioma. Archives of Pathology & Laboratory Medicine. 1987, 111:459-463.