Ann Thorac Surg 2006;82:2010-2013
© 2006 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Prognostic Factors and Surgical Indications of Pulmonary Epithelioid Hemangioendothelioma: A Review of the Literature
Patrick Bagan, MDa,
Mohammed Hassan, MDa,
Françoise Le Pimpec Barthes, MDa,
Séverine Peyrard, MSb,
Redha Souilamas, MDa,
Claire Danel, MDc,
Marc Riquet, MDa,*
a Department of Thoracic Surgery, Georges Pompidou European Hospital, Paris V University, Paris, France
c Department of Pathology, Georges Pompidou European Hospital, Paris V University, Paris, France
b Clinical Investigation Center 9201, Georges Pompidou European Hospital, Paris V University, Paris, France
Accepted for publication June 27, 2006.
* Address correspondence to Dr Riquet, Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20–40 rue Leblanc, 75908 Paris, France (Email: marc.riquet{at}egp.aphp.fr).
 |
Abstract
|
|---|
BACKGROUND: Pulmonary epithelioid hemangioendothelioma is a rare vascular tumor of low-grade malignancy, the prognosis of which remains unpredictable. The purpose of this analysis based on 80 patients was to determine prognostic factors and to evaluate results of surgery.
METHODS: We recorded data of 75 patients from reports published in the English and French literature using the terms "intravascular bronchoalveolar tumor" or "pulmonary epithelioid hemangioendothelioma" or a combination of both. We added to this database 5 more cases of pulmonary epithelioid hemangioendothelioma operated on in our thoracic surgery department from 1989 to 2005. Univariate and multivariate analyses of prognostic factors were performed using the log rank test and the Cox model. The factors we tested were age, sex, clinical symptoms, biologic and radiologic findings, and surgical treatment.
RESULTS: There were 49 women and 31 men with a mean age of 39.7 years (range, 7 to 72 years). The 5-year survival probability was 60% (range, 47% to 71%). Univariate analysis showed that loss of weight, anemia, pulmonary symptoms, and more particularly pleural hemorrhagic effusions were significant factors of poor prognosis, with a median survival of less than 1 year. Multivariate analysis showed a statistically worse survival in patients with hemorrhagic symptoms (hemoptysis, p < 0.0001; pleural effusion, p < 0.0001).
CONCLUSIONS: Pulmonary epithelioid hemangioendothelioma typically occurs among young patients. Surgery can be proposed in cases of unilateral single or multiple nodules. There is no single effective treatment in cases of bilateral multiple nodules. Lung transplantation should be evaluated in patients with vascular aggressivity with pleural hemorrhagic effusion and anemia.
|
Introduction
|
|---|
Initially known as intravascular bronchoalveolar tumor [1], pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor of borderline or low-grade malignancy. The prognosis of this tumor is unpredictable, with life expectancy ranging from 1 to 15 years [2]. We elected to study clinical, radiologic presentations, and long-term survival in reviewing published cases and patients treated in our department. The aim of this analysis based on data from 80 patients was to determine prognostic factors of PEH and to propose surgical strategy.
|
Material and Methods
|
|---|
A MEDLINE search of reports published in the English and French literature using the terms "intravascular bronchoalveolar tumor" or "pulmonary epithelioid hemangioendothelioma" or both with data including clinical symptoms, radiologic findings, methods of diagnosis treatment, and long-term follow-up yielded 40 articles [1–40]. We recorded data of 75 patients from these reports. We added to this database data from 5 patients operated on in our thoracic surgery department from 1989 to 2005 (multiple unilateral nodules, n = 2; bilateral nodules, n = 2; bilateral nodules with right pleural effusion, n = 1). Biologic data were available only in 31 patients. Our institutional review board approved this retrospective study without individual consent.
Statistical analysis was obtained by introducing the data into computerized software (StatView; Brain Power Inc, Calabasas, CA). Survival probabilities were estimated by the Kaplan–Meier method. Univariate and multivariate analyses of prognostic factors were performed using the log rank test and the Cox model. The factors we tested were age, sex, presence of thoracic symptoms (dyspnea, chest pain, hemoptysis, and cough), blood count, radiologic findings, and surgical treatment. Correlations among factors were estimated by the Fisher’s exact test. Statistical significance was found for any value of p less than 0.05. Results are presented as estimated relative risk with corresponding 95% confidence intervals.
|
Results
|
|---|
Characteristics of the patients are presented in Table 1. There were 31 men and 49 women with a mean age of 39.7 years (range, 7 to 72 years). The 5-year survival probability was 60% (range, 47% to 71%). Five-year survival of patients with pleural hemorrhagic effusion was 2%, whereas survival of population without effusion was 73% (p < 0.001; Fig 1). One-year survival of patients with anemia was 8%, whereas survival of patients without anemia was 95% (p < 0.001; Fig 2).
View larger version (12K):
[in this window]
[in a new window]
|
Fig 1. Comparative survival of patients with (solid line) and without (dashed line) pleural effusion (log rank test, p < 0.001).
|
|
View larger version (12K):
[in this window]
[in a new window]
|
Fig 2. Comparative survival of patients with (solid line) and without (dashed line) anemia (log rank test, p < 0.001).
|
|
The cause of deaths was related to PEH in 80% of cases (25 of 31 patients). In patients with bilateral disease with radiologic findings of alveolar hemorrhage (interstitial lesions, ground glasses opacities) and with hemorrhagic effusion, the cause of death was a rapid respiratory failure in the majority of cases (11 of 14 patients; 78.5%). Metastatic progression of the cancer was the cause of death in 38% of cases (9 of 12 patients), with a predominance of liver and bone metastases (Table 2).
Univariate analysis showed that loss of weight, anemia, hemoptysis, hemorrhagic pleural effusion, and related symptoms (dyspnea, cough, chest pain) were significant factors of poor prognosis. Extensive lung resection compared with wedge resection did not improve long-term survival (Table 3). Multivariate analysis showed that a statistically significant negative effect on long-term survival was achieved in patients with hemoptysis (relative risk, 5.6; 95% confidence interval, 2.5 to 12.8; p < 0.0001) or pleural hemorrhagic effusion (relative risk, 7.93; 95% confidence interval, 5.7 to 30.3; p < 0.0001). Fisher’s exact test showed a significant correlation between anemia and pleural effusion (p = 0.000005) and also between pleural effusion and thoracic symptoms (p = 0.0008).
|
Comment
|
|---|
Epithelioid hemangioendothelioma is a rare tumor affecting mainly the liver and more rarely the lung. The other organs affected are superficial or deep soft tissues of the extremities [2]. Pulmonary epithelioid hemangioendothelioma affects young patients, and is two times more common in women. The diagnosis remains difficult to establish before operation. Diagnosis is mainly obtained with pathologic examination of surgical biopsy (93% of cases) and owing to immunohistochemistry showing diffuse cytoplasmic staining of the malignant cells with factor VIII–related antigen, confirming the endothelial lineage of tumor cells. The other cell markers are antibodies against CD31 and CD34.
Once diagnosis of PEH is established, the sites of metastases (Table 2) imply systematic inclusion of pulmonary, liver, and brain computed tomographic scans and bone scintigraphy in the workup and during the follow-up. Liver metastasis does not have the same significance as for typical lung cancers because of the possibility of both a multicentric primary tumor or a pulmonary tumor with metastases. Distinction between multifocal disease and metastatic progression is difficult, but bifocal hepatic and pulmonary location at diagnosis is not considered as metastatic disease by surgeons who manage transplantation for hepatic hemangioendothelioma [41].
In reviewing long-term survival, we observed that the current staging system for lung carcinoma does not predict outcome for PEH. As proposed by Ebright and colleagues [36] for bronchioloalveolar carcinoma, clinical and radiologic disease pattern is more appropriate for the prognosis of PEH. The PEH population can be divided into two groups according to clinical and radiologic findings: asymptomatic patients with nodules who have a median survival of 180 months, and patients with symptoms of vascular endothelial cell proliferation (alveolar hemorrhage, hemoptysis, hemorrhagic pleural effusion, anemia) who have a significantly worse survival. Our analysis supports statistically the clinical observation made first in 1998 [24] that the most significant symptom of vascular aggressiveness and poor survival is pleural hemorrhagic effusion. It is also significantly correlated with anemia and with thoracic symptoms. The most representative recent case was reported by Rossi and colleagues in 2003 [30]: a 14-year-old boy with multiple interstitial lesions with bilateral hemorrhagic effusion who died 3 months after diagnosis of PEH because of restrictive respiratory failure despite pleurodesis.
Because of the rarity of PEH, there is no standard for treatment. In patients with a unilateral nodule, wedge resection offers the same survival as that observed after anatomic resection (p = 0.1543). Hilar lymph node resection should be proposed systematically, but the prognostic value of lymph node invasion remains statistically unclear because of the low number of patients (9% of patients with lymph node metastases [2]).
In patients with bilateral nodules, partial or complete response has been reported with interferon 
2a [17, 37], and three partial spontaneous regression have also been described [24]. The other treatments proposed are corticosteroids [33], azathioprine [8, 34], multiple wedge resections [24], or simple follow-up.
In patients with hemorrhagic symptoms, only one report described a complete response to carboplatin plus etoposide chemotherapy [36]; other treatments including major pulmonary resection were unsuccessful [23]. Pleural hemorrhagic effusion with related symptoms such as anemia, chest pain, chronic cough, and hemoptysis reflects the aggressiveness of the disease. The main cause of death in this group is respiratory failure, and no efficient treatment is currently available. In case of hepatic hemangioendothelioma, patients with advanced liver disease are demonstrated to benefit from transplantation with good results [41, 42]. The more important series [38] reports a patient survival of 71.3% at 5 years and a 5-year disease-free survival of 60.2%. This 5-year survival compares favorably with that of hepatocellular carcinoma at the same stage even in the presence of limited metastases, and a recent series also demonstrates liver transplantation to be a valuable treatment in cases of hepatic hemangioendothelioma, even when extrahepatic locations of the disease are present [39]. We suggest that lung transplantation should be advocated as an alternative treatment fo PEH that is dramatically evolving to restrictive respiratory failure.
In conclusion, prognosis of PEH depends on vascular aggressiveness markers of hemorrhagic symptoms (pleural effusion, alveolar hemorrhage, anemia). Surgery can be proposed in cases of unilateral single or multiple nodules. There is no single effective treatment in cases of bilateral multiple nodules. Lung transplantation should be evaluated in cases of vascular aggressiveness because of the life expectancy of less than 1 year.
|
References
|
|---|
- Dail DH, Liebow AA, Gmelich JT. 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.[Medline]
- Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature Chest 2004;125:789-792.
- Weldon-Linne CM, Victor TA, Christ ML. Angiogenic nature of the "intravascular bronchioalveolar tumor of the lung": an electron microscopic study Arch Pathol Lab Med 1981;105:174-179.[Medline]
- Yousem SA, Hochholzer L. Unusual Thoracic manifestations of epithelioid hemangioendothelioma Arch Pathol Lab Med 1987;111:459-463.[Medline]
- Struhar D, Sorkin P. Alveolar haemorrhage with pleural effusion as a manifestation of epithelioid haemangioendothelioma Eur Respir J 1992;5:592-593.[Abstract]
- Briens E, Caulet-Maugendre S. Alveolar haemorrhage revealing epithelioid haemangioendothelioma Respir Med 1997;91:111-114.[Medline]
- Jang KY, Jin GY. Pulmonary epithelioid haemangioendothelioma: a tumor presented as a single cavitary mass J Korean Med Sci 2003;18:599-602.[Medline]
- Ledson MJ, Convery R, Carty A, et al. Epithelioid haemangioendothelioma Thorax 1999;54:560-561.[Abstract/Free Full Text]
- Just N, Tavernier JY. Hémangioendothéliome épithélioide multifocal de diagnostic difficile Rev Mal Respir 2003;20:761-765.[Medline]
- Van Kasteren MEE, Van der Wurff AAM. Epithelioid haemangioendothelioma of the lung: clinical and pathological pitfalls Eur Respir J 1995;8:1616-1619.[Abstract]
- Bhagavan BS, Dorfman HD. Intravascular bronchiolo-alveolar tumor (IVBAT): a low-grade sclerosing epithelioid angiosarcoma of lung Am J Surg Pathol 1982;6:41-52.[Medline]
- Carter EJ, Bradburne RM. Alveolar hemorrhage with epithelioid hemangioendothelioma Am Rev Respir Dis 1990;142:700-701.[Medline]
- Wenisch HJC, Lulay M. Lymphogenous spread of an intravascular bronchioalveolar tumor Virchows Arch A Path Anat Histol 1980;387:117-123.
- Poletti V, Casadei G. Epithelioid haemangioendothelioma of the lung imitating clinical features of pulmonary histiocytosis X Monaldi Arch Chest Dis 1997;52:346-348.[Medline]
- Kradin RL, Mark EJ. Case records of the Massachusetts General Hospital N Engl J Med 2000;342:572-578.[Free Full Text]
- Paciocco G, Caterino U, D’Auria D. Epithelioid haemangioendothelioma of the lung: a high malignancy case Monaldi Arch Chest Dis 1999;54:231-233.[Medline]
- Erasmus JJ, McAdams HP. Roentgenogram of the month: a 63-year-old woman with weight loss and multiple lung nodules Chest 1997;111:236-238.
- Hubscher PH, El Haite A. Lâcher de ballons de cause inhabituelle Rev Mal Respir 2000;17:704-706.[Medline]
- Charlier C, Hamel B. Nodules pulmonaires multiples avec signe du halo Rev Mal Respir 2003;20:459-461.[Medline]
- Rock MJ, Kaufman RA. Epithelioid hemangioendothelioma of the lung (intravascular bronchioloalveolar tumor) in a young girl Pediatr Pulmonol 1991;11:181-186.[Medline]
- Roepke JE, Heiftez SA. Pathological case of the month Arch Pediatr Adolzsc Med 1997;151:317-319.
- Emery AW, Fox AL. Short reports (intravascular bronchioloalveolar tumour) Thorax 1982;37:472-473.[Free Full Text]
- Kitaichi M, Nagai S. Pulmonary epithelioid haemangioendothelioma in 21 patients including three with partial spontaneous regression Eur Respir J 1998;12:89-96.[Abstract]
- Kantelip B, Champiat B, Mignot P. Intravascular bronchioloalveolar tumor ou (IVBAT): un propos d’un cas et revue de la litterature Rev Pneumol Clin 1985;41:273-282.[Medline]
- Borlee-Hermmans G, Bury T. Intravascular bronchioloalveolar tumour Eur J Respir Dis 1985;66:341-346.[Medline]
- Sicilian L, Warson F, Carrington CB. Intravascular bronchioloalveolar tumor (IV-BAT) Respiration 1983;44:387-394.[Medline]
- Sweeney WB, Vesoulis Z, Blaum Jr LC. Intravascular bronchioalveolar tumor: a distinctive surgical and pathological entity Ann Thorac Surg 1986;42:702-704.[Abstract]
- Diaz R, Segura A, Calderero V, et al. Central nervous system metastases of a pulmonary epithelioid hemangioendothelioma Eur Respir J 2004;23:483-486.[Abstract/Free Full Text]
- Rossi GA, Toma P, Sacco O, et al. A 14-yr-old male with dyspnea, productive cough and chest pain Eur Respir J 2003;22:387-391.[Free Full Text]
- Sherman JL, Rykwalder PJ, Tashkin DP. Intravascular bronchiolo-alveolar tumor Am Rev Resp Dis 1981;123:468-470.[Medline]
- Ferrer-Roca O. Intravascular and sclerosing bronchio-alveolar tumor Am J Surg Pathol 1980;4:375-381.[Medline]
- Azumi N, Churg A. Intravascular and sclerosing bronchioloalveolar tumorA pulmonary sarcoma of probable vascular origin. Am J Surg Pathol 1981;5:587-596.[Medline]
- Marsch K, Kenyon WE, Earis JE, et al. Intravascular bronchioalveolar tumor Thorax 1982;37:474-475.[Free Full Text]
- Miettinen M, Collan Y, Halttunen P, et al. Intravascular bronchioloalveolar tumor Cancer 1987;15:2471-2475.
- Pinet C, Magnau A, Garbe C, et al. Aggressive form of pleural epithelioid hemangioendothelioma: complete response after chemotherapy Eur J Respir 1999;92:116-121.
- Ebright MI, Zakowski MF, Martin J, et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioalveolar carcinoma Ann Thorac Surg 2002;74:1640-1647.[Abstract/Free Full Text]
- Roudier-Pujol C, Enjolras O, Lacronique J, et al. Multicentric epithelioid hemangioendothelioma in partial remission with interferon treatment Ann Dermatol Venereol 1994;121:898-904.[Medline]
- Lantuejoul S, Esvant H, Brambilla C, Brambilla E. Pulmonary epithelioid hemangioendothelioma (or IVBAT): report of a case of exclusively myxoid form Ann Pathol 1997;17:120-122.[Medline]
- Clary C, Jacob C, Blaive B, Kermarec J. Intravascular bronchiolo-alveolar tumorStudy of a form with angiosarcomatous tendency. Ann Pathol 1985;5:107-114.[Medline]
- De-Luca S, Sanguinetti CM, Bearzi I, Murer B. Intravascular bronchioalveolar tumour Eur Respir J 1990;3:346-348.[Abstract]
- Madariaga JR, Marino IR, Karavias DD. Long-term results after liver transplantation for primary hepatic epithelioid hemangioendothelioma Ann Surg Oncol 1995;2:483-487.[Abstract]
- Lerut JP, Orlando G, Sempoux C, et al. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation Transpl Int 2004;17:202-207.[Medline]
Top
Abstract
Introduction
