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A 40-Year-Old Woman With Multilobar Nodular Densities and Massive HemoptysisA Woman With Massive Hemoptysis FREE TO VIEW

Jeffrey Albores, MD; Joanne Bando, MD; Igor Barjaktarevic, MD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

CORRESPONDENCE TO: Jeffrey Albores, MD, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 37-131 CHS, Los Angeles CA 90095; e-mail: jalbores@mednet.ucla.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(4):e134-e137. doi:10.1378/chest.13-2927
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A 40-year-old white woman presented with 1-week history of mild cough, fever, and progressive nonmassive bright-red blood hemoptysis. She denied dyspnea, sputum production, epistaxis, hematemesis, or weight loss. She was an active smoker for the past 20 years with history of chronic pancreatitis and chronic pain requiring jejunal tube feeding and chronic IV analgesics. She had no history of malignancy or lung disease and had been in her usual state of health until the symptom onset a week prior.

Physical examination revealed a BP of 120/70 mm Hg; pulse, 100 beats/min; respiratory rate, 22 breaths/min; temperature, 37°C; and oxygen saturation 95% on room air. She was in mild respiratory distress with persistent cough and hemoptysis. Lung examination revealed decreased breath sounds at the right base with diffuse crackles; the rest of the examination was unremarkable.

The patient had mild leukocytosis (WBC count, 14,000/μL) with neutrophilic predominance and normal coagulation study results. Chest radiograph showed consolidation in the right lower lobe (Fig 1).

Figure Jump LinkFigure 1 –  Initial chest radiograph showing consolidation of the right lower lobe. In addition, cardiac silhouette is borderline enlarged and a tunneled left-sided central line with its tip is in the right atrium.Grahic Jump Location

She was initiated on a community-acquired pneumonia antibiotic regimen but her condition continued to worsen with persistent massive hemoptysis associated with dyspnea and oxygen desaturation. Chest CT scan showed multiple scattered mass-like nodular opacities involving bilateral lungs (Fig 2). Multiple bronchoscopies revealed continuous blood oozing from the right middle lobe so she underwent selective right bronchial artery embolization; BAL and transbronchial biopsy specimen analyses were negative for infectious or malignant etiologies. As her hemoptysis persisted, she underwent video-assisted thoracoscopic surgery with right middle lobectomy. Pathology of the lung nodules revealed areas of significant hemorrhage and necrosis and an extensive proliferation of round-shaped to oval-shaped epithelioid cells. Immunohistochemical stains were positive for ETS-related gene (ERG), CD31, and Fli-1 (Fig 3). These findings were also noted in the intrathoracic lymph nodes and pericardial nodule.

Figure Jump LinkFigure 2 –  A, B, Chest CT scan showing multiple scattered mass-like nodular opacities, the largest measuring 4.0 × 2.7 cm in the right lower lobe. A, Tranverse cuts. B, Coronal cut. Multiple additional nodular opacities are identified in the right upper, left upper, and left lower lobes. Some of the nodules have a subpleural component. There is a small right-sided pleural effusion. In addition, there is significant intrathoracic lymphadenopathy with enlarged paratracheal and bilateral hilar lymph nodes.Grahic Jump Location
Figure Jump LinkFigure 3 –  Surgical lung biopsy of the right middle lobe. A, Low-power view showing the lung mass tissue surrounded by lung parenchyma (hematoxylin and eosin [H&E] stain, magnification × 20). B, Higher magnification of the lung mass tissue showing epithelioid cells set in a collagenous matrix (H&E stain, magnification × 400). C, Immunohistochemical stain positive for CD31 (magnification × 200). D) Immunohistochemical stain positive for ETS-related gene (ERG) (magnification × 200). The immunohistochemical stains were also positive for CD30 and Fli-1. The intrathoracic lymph nodes also showed in the previously mentioned findings.Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary epithelioid hemangioendothelioma

Pulmonary epithelioid hemangioendothelioma (EHE) was first described in 1975 and was initially considered an aggressive form of bronchoalveolar cell carcinoma invading adjacent blood vessels, hence, the original name intravascular bronchoalveolar tumor. Soon after, the advent of immunohistochemical techniques confirmed diffuse cytoplasmic staining of the malignant cells with factor VIII-related antigen that further allowed the categorization of pulmonary EHE as a tumor of endothelial lineage. In 1982, the term “epithelioid hemangioendothelioma” was coined, and EHE was described as a rare vascular tumor of borderline or low-grade malignancy that is both clinically and histologically intermediate between benign hemangioma and malignant angiosarcoma. EHE is of multicentric origin, and extrapulmonary lesions arise from the liver, bone, soft tissue, and skin. The lungs are rarely involved, with only approximately 100 cases of pulmonary EHE described in literature.

Pulmonary EHE usually presents with multiple pulmonary nodules in patients with no risk factors for malignancy. It is two to three times more common in women and is most commonly found among middle-aged patients. Patients with pulmonary EHE are usually asymptomatic at the time of diagnosis and are often diagnosed incidentally. In symptomatic patients, dyspnea, cough, chest pain, hemoptysis, and weight loss are most common findings.

The most characteristic feature of pulmonary EHE on imaging is its multifocality and the presence of multiple perivascular nodules with well-defined or ill-defined margins in both lungs. The nodules vary in size and are usually adjacent to small and medium-sized vessels and bronchi. Radiographically, bilateral multiple nodular opacities are the most common initial presentation. Pulmonary EHE may also present as nodular pleural involvement and pleural effusion. Pulmonary EHE is often difficult to diagnose and diagnosis is often delayed. Lung biopsy is usually necessary and, whereas open surgical or thoracoscopic biopsies are most often required, there are case reports of diagnosis with transbronchial biopsies. Pleural fluid has been characterized as exudative (with lymphocytic predominance) or hemorrhagic, but cytologic evaluation is, typically, inadequate to make a definitive diagnosis. The diagnosis of pulmonary EHE is conducted on the basis of histologic features and confirmed with immunohistochemistry. Pulmonary EHE is characterized by immunoreactivity to some or all of the vascular endothelial markers (CD31, CD34, and factor VIII). EHE can be distinguished from a carcinoma by the lack of pleomorphism and mitotic activity and the presence of focal vascular channels.

The natural history of EHE is difficult to predict. Patients are diagnosed with EHE at different stages of their disease. EHE usually has a slow pace of tumor growth rate with prolonged periods of stability but is not uniform during the course of the disease and can escalate during later stages. During the indolent course, patients may live for up to 15 to 20 years after initial diagnosis. Cases diagnosed with advanced disease have been reported but it is unclear whether these patients were diagnosed later in the disease stage or if this subset of patients with EHE has an aggressive behavior. Poor prognostic factors for pulmonary EHE include the presence of respiratory symptoms or malignant pleural effusion; extensive intravascular, endobronchial, or interstitial tumor spreading; hepatic metastases; peripheral lymphadenopathy; presence of spindle cells in the tumor; and, particularly, pleural hemorrhagic effusions and hemoptysis. In patients with pleural hemorrhagic effusion or hemoptysis, the median survival is < 1 year.

Due to the rarity of pulmonary EHE, there is no clear standard of treatment in the absence of well-defined clinical trials. Partial spontaneous regressions have been described and watchful waiting has been reported to be an acceptable option, particularly in asymptomatic patients. Progressive or symptomatic disease may require treatment. Surgical resection may be performed for local disease control in cases of unilateral disease; but often, this is not an option because the presentation is, typically, bilateral and multifocal at diagnosis. Systemic therapy options have been poorly studied in EHE. Although the outlook can be grim, patients with poor prognostic markers or a more aggressive course may benefit from chemotherapy as suggested by a small case series that demonstrated some regression of tumor size and symptoms after treatment with (or a combination of) carboplatin, paclitaxel, bevacizumab, thalidomide, and α-interferon. Given the endothelial origin of EHE and in the absence of active bleeding, the antagonists of vascular endothelial growth factor may potentially play a significant role in the treatment of EHE.

Clinical Course

Pathology from the right middle lobe revealed pulmonary epithelioid hemangioendothelioma (Fig 3). Sampled mediastinal lymph nodes confirmed the involvement with EHE. The patient had persistent hemoptysis despite the right middle lobectomy. She was referred to a sarcoma specialist. As her disease was advanced, systemic chemotherapy with a combination of gemcitabine, taxotere, and adriamycin was initiated. Given the patient’s bleeding, antiangiogenesis agents were not tried. She had resolution of her hemoptysis and at 2-months’ follow-up after initiation of chemotherapy, she had a decrease in size of her pulmonary masses. However, 5 months later, the patient had worsening dyspnea and interval chest CT scan showed an increase in size of the pulmonary masses with associated areas of pulmonary hemorrhage despite chemotherapy. The patient died of respiratory failure and infectious complications.

  • 1. Pulmonary EHE is a rare vascular tumor most commonly presenting with nonspecific multinodular pulmonary opacities with an appearance that may not impress as primary lung malignancy.

  • 2. Histopathologic examination of the surgical lung biopsy specimen with immunohistochemical staining for vascular endothelial markers is necessary to confirm the diagnosis of pulmonary EHE.

  • 3. Pulmonary EHE usually has an indolent course and asymptomatic patients may be observed without therapy.

  • 4. There has been no standard treatment of pulmonary EHE but patients with a more aggressive course or poor prognostic markers (hemoptysis, pleural hemorrhagic effusion, respiratory symptoms) may benefit from combination chemotherapy based on a small case series.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Dean Wallace, MD, and Sarah Dry, MD, Department of Pathology, UCLA, for assistance with the pathology illustrations. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970-981. [CrossRef] [PubMed]
 
Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125(2):789-793. [CrossRef] [PubMed]
 
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(6):818-825. [CrossRef] [PubMed]
 
Ravi V, Patel S. Vascular sarcomas. Curr Oncol Rep. 2013;15(4):347-355. [CrossRef] [PubMed]
 
Ye B, Li W, Feng J, Shi JX, Chen Y, Han BH. Treatment of pulmonary epithelioid hemangioendothelioma with combination chemotherapy: report of three cases and review of the literature. Oncol Lett. 2013;5(5):1491-1496. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Initial chest radiograph showing consolidation of the right lower lobe. In addition, cardiac silhouette is borderline enlarged and a tunneled left-sided central line with its tip is in the right atrium.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, Chest CT scan showing multiple scattered mass-like nodular opacities, the largest measuring 4.0 × 2.7 cm in the right lower lobe. A, Tranverse cuts. B, Coronal cut. Multiple additional nodular opacities are identified in the right upper, left upper, and left lower lobes. Some of the nodules have a subpleural component. There is a small right-sided pleural effusion. In addition, there is significant intrathoracic lymphadenopathy with enlarged paratracheal and bilateral hilar lymph nodes.Grahic Jump Location
Figure Jump LinkFigure 3 –  Surgical lung biopsy of the right middle lobe. A, Low-power view showing the lung mass tissue surrounded by lung parenchyma (hematoxylin and eosin [H&E] stain, magnification × 20). B, Higher magnification of the lung mass tissue showing epithelioid cells set in a collagenous matrix (H&E stain, magnification × 400). C, Immunohistochemical stain positive for CD31 (magnification × 200). D) Immunohistochemical stain positive for ETS-related gene (ERG) (magnification × 200). The immunohistochemical stains were also positive for CD30 and Fli-1. The intrathoracic lymph nodes also showed in the previously mentioned findings.Grahic Jump Location

Tables

Suggested Readings

Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970-981. [CrossRef] [PubMed]
 
Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125(2):789-793. [CrossRef] [PubMed]
 
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(6):818-825. [CrossRef] [PubMed]
 
Ravi V, Patel S. Vascular sarcomas. Curr Oncol Rep. 2013;15(4):347-355. [CrossRef] [PubMed]
 
Ye B, Li W, Feng J, Shi JX, Chen Y, Han BH. Treatment of pulmonary epithelioid hemangioendothelioma with combination chemotherapy: report of three cases and review of the literature. Oncol Lett. 2013;5(5):1491-1496. [PubMed]
 
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