—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 1 - Epithelioid Hemangioendothelioma

Lindsay A. Schmidt, University of Michigan, Ann Arbor, MI





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Introduction:
Patient is a 12-year-old previously healthy girl who presented to her primary care physician with fatigue and significant (approximately 25 pounds) unintentional weight loss over the previous 6 months. Two weeks prior to presentation, she also developed a productive cough and vomiting. Her mother noticed nail changes as well. She had no significant travel or infectious exposures. She had been treated for pneumonia at age 4. She lives in a rural location, with exposure to hay in a barn. On physical exam, she was found to have very faint bibasilar crackles as well as clubbing of her finger and toenails. Plain chest x-ray was found to have diffuse reticulonodular pattern. Laboratory findings show a normal sweat chloride test. She had mild restrictive findings on pulmonary function testing. Clinically, she was suspected to have sarcoidosis, infection, or hypersensitivity pneumonia. A wedge biopsy was performed for diagnosis.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Microscopic Description: Sections demonstrate multiple round nodules within pulmonary parenchyma. These nodules have a central hypocellular zone with abundant myxoid matrix surrounded by a cellular zone. Tumor cells compose with cellular periphery and are embedded within the central matrix. The tumor cells are epithelioid with prominent eosinophilic cytoplasm. Tumor nuclei are round to oval with open chromatin and one or two small nucleoli. The tumor cells are bland, and mitotic figures are difficult to find. Rare tumor cells have a single prominent intracytoplasmic vacuole. Tumor cells are also present within lymphatic spaces in the pleura and are spreading along vascular structures. Tumor cells are positive for CD34, CD31, and Factor VIII, which highlights intracytoplasmic vacuoles.


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Differential Diagnoses:
Epithelioid hemangioendothelioma

Chondrosarcoma

Angiosacoma

Adenocarcinoma

Final Diagnosis:
Epithelioid hemangioendothelioma

Case 1

Discussion: Dail and Liebow first described this unusual thoracic tumor in a case series in 1975 [1] . At that time, they surmised that the tumor was derived from bronchioloalveolar cells with a high rate of vascular invasion, leading to the name intravascular bronchiolo-alveolar tumor (IVBAT). Cases contained in the literature prior to this were reported under several different names, including "chondrosarcomatosis" and "pulmonary deciduosis" [2] . Subsequent immunohistochemical and ultrastructural studies demonstrated that this neoplasm was derived from endothelial cells [3, 4, 5, 6] . Consequently Weiss and Enzinger recognized that this entity was the lung's counterpart to epithelioid hemangioendothelioma (EHE) seen in other organs [7] . Pulmonary EHE is now recognized as a low-to-intermediate grade vascular neoplasm by the 2004 WHO Classification of lung tumors [8] .

Pulmonary EHE is now known to have a marked predilection for females [9, 10, 11] . EHE can have a wide age range, occurring in the adolescent population as well as patients in their seventies, with a mean age at presentation of 40 years. There are no known exposures that are risk factors for the development of EHE [9] . P ulmonary EHE is incidentally discovered in asymptomatic patients in about half of known cases [12] . In patients who do present with symptoms, cough and chest pain are the most common; uncommon presenting signs and symptoms include hemoptysis and digital clubbing [12] . Men are more likely to be asymptomatic than women. There are reported cases of patients presenting with the signs and symptoms of pulmonary Langerhans' cell histiocytosis with spontaneous pneumothorax [13] and with acute pulmonary thromboembolic disease and pulmonary hypertension [14] . Radiographic findings in pulmonary EHE are diverse, with most patients presenting with multiple unilateral or bilateral nodules mimicking widely metastatic carcinoma [9, 10, 12, 15, 16, 17, 18] . Occasionally, these nodules can become calcified [16, 18], and tend to be very slow growing, with reports of nodules remaining stable for ten to twenty years [16] . Pulmonary EHE is also known to occasionally present with a pattern mimicking interstitial lung disease on chest imaging, including bilateral parenchymal opacities, increased interstitial markings, ground glass opacities, and nonspecific thickening of bronchovascular bundles [9, 15, 17, 19] .

The classic histologic features of pulmonary EHE include round to oval shaped nodules which have a central hypocellular zone surrounded by a cellular peripheral zone. The center of the nodule can become calcified. The tumor classically involves and spreads along vascular structures and airways. Within the alveolar spaces, tumor cells spread into adjacent alveoli through pores of Kohn. The cells are embedded within a matrix that can be myxoid, hyaline, or chondroid. The cells themselves are epithelioid with eosinophilic cytoplasm, occasionally containing a single intracytoplasmic lumen. Tumor nuclei are round to oval with dispersed chromatin and small nucleoli. Variants have been reported with prominent plasmacytoid morphology and numerous intracytoplasmic vacuoles mimicking signet ring cell carcinoma [20] and rhabdoid features with abundant eosinophilic cytoplasm displacing the nucleus [21] . Immunohistochemistry can be very helpful in identifying EHE, with tumor cells marking with various endothelial markers including CD31, CD34, and Factor VIII in the majority of cases. Ultrastructurally, tumor cells have been shown to contain desmosomal intracellular junctions, microfilaments, pinocytotic vesicles, large central vacuoles, and Wiebel-Palade bodies [3, 4, 6, 22] .

Numerous variants of pulmonary EHE have been described, including anterior mediastinal lesions [23] . Pleural involvement by EHE is well-described, with a tumor rind extending into parenchyma along fissures and interlobular septae, grossly and radiographically mimicking malignant mesothelioma [21, 24, 25, 26, 27, 28, 29] . Patients with pleural involvement tend to be older and have a worse prognosis than those with pulmonary involvement only [25, 29] .

Mean survival in patients with pulmonary EHE is between 5 and 10 years, although cases with long-term stable disease and even spontaneous regression have been described [11, 12] . Poor prognostic indicators include male sex, symptomatic presentation (especially cough and hemoptysis), weight loss, anemia, metastases to more than one site, nodal involvement, pleural effusion (especially hemorrhagic effusion), and pleural involvement [9, 11, 12] . Histologically, poor prognostic features include fibrous pleuritis, extrapleural proliferation of tumor, and spindled cells [11] . There is no current standard therapy available for pulmonary EHE. Wedge resection versus larger resection has shown no survival difference [9] . Chemotherapeutic options include alpha-interferon, steroids, azathioprine, and platinum-based chemotherapies, though none have shown consistent survival advantages. Additional therapeutic options suggested in the literature include lung transplantation [9] and vascular endothelial growth factor (VEGF) inhibitors [30] .

The differential diagnosis of pulmonary EHE includes metastatic lesions, including both metastatic adenocarcinoma (especially in cases demonstrating prominent signet ring cell morphology) and metastatic sarcomas (especially epithelioid angiosarcoma). Immunohistochemical staining strategies should be aimed at demonstrating an endothelial phenotype (CD31, CD34, and Factor VIII). Keratin staining has been reported in some cases and must be interpreted with caution. Differentiating EHE from angiosarcoma can be difficult. Features that favor a diagnosis of angiosarcoma include marked nuclear atypia, increased mitotic activity, and anastomosing vascular channel formation [30, 31, 32] . In the pleura, both EHE and angiosarcoma have a poor prognosis; however angiosarcoma tends to behave worse than EHE in the pleura.

Conclusion(s):
Pulmonary EHE is an unusual neoplasm which can have numerous diverse presentations, including nodules, pleural disease, and interstitial changes. The differential diagnosis includes metastatic carcinoma, angiosarcoma, and mesothelioma. An immunohistochemical panel including endothelial markers can be helpful in distinguishing these entities.

References:
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  2. Farinacci CJ, Blauw AS,Jennings EM. Multifocal pulmonary lesions of possible decidual origin (so-called pulmonary deciduosis): report of a case. Am J Clin Pathol. 1973;59:508-14.

  3. Bhagavan BS, Dorfman HD, Murthy MS, et al. Intravascular bronchiolo-alveolar tumor (IVBAT): A low-grade sclerosing epithelioid angiosarcoma of lung. Am J Surg Pathol. 1982;6:41-52.

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  19. Mukundan G, Urban BA, Askin FB, et al. Pulmonary epithelioid hemangioendothelioma: atypical radiologic findings of a rare tumor with pathologic correlation. J Comput Assist Tomogr. 2000;24:719-20.

  20. Hristova EN, Krishnamurthy S, Ro JY, et al. Pulmonary epithelioid hemangioendothelioma with prominent signet ring cell features mimicking metastatic adenocarcinoma. Ann Diagn Pathol. 2003;7:160-4.

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  29. Lin BT, Colby T, Gown AM, et al. Malignant vascular tumors of the serous membranes mimicking mesothelioma. A report of 14 cases. Am J Surg Pathol. 1996;20:1431-9.

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