Diagnosis: Multifocal epithelioid hemangioendothelioma of lung
Pulmonary Epithelioid Hemangioendothelioma (EH)
Introduction: Pulmonary EH (previous terms: primary chondrosarcoma; pulmonary deciduosis; intravascular, bronchiolar, and alveolar tumor (IVBAT) ), is now considered to be another manifestation of EH that occurs in other parts of the body including soft tissues, bone, liver, breast, brain, meninges, or lymph nodes [2-4]. It is a rare, low-grade, sclerosing angiosarcoma. It may involve the lung alone in a multifocal fashion or be accompanied by tumor in other organs [2,3]. Whether these tumors arise multicentrically or represent metastases is not known. The term epithelioid refers to the abundance of cytoplasm that makes the neoplastic cell resemble an epithelial cell. These tumors, which are unpredictable in their clinical course, are nevertheless intermediate in their behavior between benign hemangiomas and angiosarcomas .
EH also occurs in the liver as a primary organ, where it also has an unpredictable course. The possibility of a relation of liver tumors to use of oral contraceptive drugs has been raised (5 women (ages 27-42) with hepatic EH had used them) . Ten patients have undergone liver transplant for the disease. Extrahepatic spread at presentation was not a contraindication for transplant and did not change the outcome (5-y survival rate of 76%) [6,7].
Clinical features: EH of the lung is asymptomatic in about 1/2 of cases and occurs mainly in young women (F:M, 3.8:1). The average age is 37 y (range is 7 to 69), and about 1/2 of cases are under age 40. There appears to be a bimodal distribution of ages with peaks in the third and fifth decades (graph). Symptoms or signs, when present, include chest pain, dyspnea, cough, pleurisy, weight loss, and clubbing . Symptoms of extrapulmonary disease may precede or follow the diagnosis of lung disease.
Graph (53 patients) [1,3,8,10-30]
Radiographic features: Typically, this disease presents with multifocal nodules up to 2 cm with well- or poorly-defined margins ± central calcification. In 2 cases studied by CT, the nodules showed a perivascular distribution, and in one case involvement of the interlobular septa was noted, as well. In these 2 cases there was little or no change over 10 or 20 y, respectively, although calcification at the periphery of the nodule was noted in the case examined after 20 y . Infrequently, the disease produces focal or diffuse pleural thickening; large, solitary pulmonary nodules; or few nodules [1,3]. The radiographic differential diagnosis includes metastatic neoplasm, primary bronchioloalveolar carcinoma, and infectious granulomatous disease, as well as sarcoidosis.
Gross features: Tumor forms circumscribed, translucent nodules resembling and cutting like cartilage. There may be central opacity and calcification that suggest necrosis. Involvement of visible vessels or airways is rare . Subpleural nodules cause retraction of the pleura and produce overlying pleural indentation .
Histologic features: The pulmonary nodules are not encapsulated. They have cellular peripheral zones and hypocellular, pink centers. Unlike other tumors, EH grows into alveolar spaces, bronchioles, and vessels without completely destroying the architecture. This growth pattern gives a microlobulated appearance. A chondromyxoid (homogeneous bluish to loose bluish) stroma, believed to be produced by the tumor cells, increases from the periphery toward the center, where cells and alveolar walls become compressed and undergo coagulative necrosis. Dystrophic calcification and organization may also occur in the necrotic centers of the tumor. Surrounding alveoli are normal and not compressed. They are lined by hyperplastic type II cells, which must be distinguished from the tumor cells. A mild lymphoplasmacellular infiltrate is also present in the adjacent lung but not in the tumor. Occasionally, tumor invades the interstitial space around blood vessels, the interlobular septa, or the pleura. Sometimes there is a prominent intralymphatic component , and in some tumors a pleural or lymphangitic pattern predominates [1,3].
Tumor cells at the periphery have abundant pink cytoplasm. Cell borders may be well-defined or blend in with the stroma. Nuclei are rounded with peripherally condensed chromatin and prominent nucleoli. Mitoses are very rare (<1 per 10 high power fields). Toward the center, cells become compressed, lie in lacunar spaces, and resemble cartilage . Tumors with prominent cellular pleomorphism, solid cellular areas, and a mitotic rate greater than 1/10 high power fields should be classified as high-grade angiosarcoma .
Immunohistochemistry: The vascular nature of the tumor is confirmed by demonstration of its reactivity with one or more of the following: Ulex europeus-1 (a lectin that binds to endothelial cells), anti-Factor VIII-related antigen, anti-CD-31 (platelet endothelial cell adhesion molecule (PECAM 1)), and anti-CD-34 (an antigen found on hematopoietic and endothelial stem cells) [9-11].
Ultrastructural findings: Electron microscopic examination of the tumors shows an endothelial phenotype. Besides microfilaments, rough endoplasmic reticulum, and lysosomes, tumor cells contain Weibel-Palade bodies . These bodies (see diagram) are elongate, multitubular structures (1 to 2.5 µm by 0.1 µm) that have been found only in endothelial cells. EM also shows that tumor cells sometimes have cytoplasmic vacuoles (intracellular lumens) and sometimes form small vascular structures. Cells are surrounded, in part, by a basement membrane and are embedded in a matrix of collagen, elastin, and ground substance [10-12].
Cytopathology: Cytologic preparations from fluids can suggest or confirm a histologic diagnosis [11,13].
Cytogenetics: In one case with involvement of soft tissues of the back, lung, and bone, cytogenetic analysis of the soft tissue tumor showed a translocation involving chromosomes 7 and 22, a translocation involving the chromosome 14 pair, and deletion of the Y chromosome .
Histologic differential diagnosis: Non-neoplastic conditions that have been considered include infectious granulomas, organizing infarcts, alveolar proteinosis, and amyloid nodules. Benign neoplasms to be considered include hamartomas and minute meningotheliomatous nodules . Malignant neoplasms include diffuse malignant mesothelioma , primary bronchioloalveolar carcinoma, adenoid cystic carcinoma, chondro(myxo)sarcoma, leiomyosarcoma, and angiosarcoma .
Treatment and course: Occasional patients have been treated with chemotherapy or radiation without response. Most patients are not treated. Death from disease is usually due to respiratory failure. Mean survival for 26 patients was a little over 5 y, with survival up to 24 y. Patients with clinical symptoms or widespread intravascular, endobronchial, interstitial, or pleural involvement have a worse prognosis .
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Last revised 2/3/98
Copyright 1998 by Martha L. Warnock. All rights reserved.
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