Case 1 -

Pleural Epithelioid Hemangioendothelioma Samuel A. Yousem University of Pittsburgh Medical Center Pittsburgh, PA

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Clinical History: 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 Click to view with ImageScope Click to view with a Web-Based Viewer 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. Diagnosis: Pleural epithelioid hemangioendothelioma. Discussion: 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 "carcinomatosis". 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. References: 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. 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