Epithelioid Hemangioendothelioma in Pleural Effusion Maryam Sayah, MD,1 Christopher VandenBussche, and Zahra Maleki, MD2*
Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin with variable morphological features and unpredictable biological behavior. EHE occasionally involves the pleural fluid. However, the cytomorphology of EHE found in pleural fluid has not been well characterized in the literature. Herein we describe a case of EHE, initially presenting as multiple liver lesions plus several small nodular densities at the bases of the lungs followed by bilateral pleural effusions. C 2015 Wiley Periodicals, Diagn. Cytopathol. 2015;43:751–755. V Inc. Key Words: pleural effusion; cytology; epithelioid hemangioendothelioma; vascular neoplasm
Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin with variable morphological features and unpredictable biological behavior. In 1982, EHE was first described by Weiss and Enzinger as a low-grade angiosarcoma.1 While these lesions are sometimes diagnosed on the fine-needle aspiration of a solid lesion, EHE occasionally involves the pleural fluid. However, the cytomorphology of EHE found in pleural fluid has not been well characterized in literature. Here we describe a case of EHE, initially presenting as multiple liver lesions plus several small nodular densities at the bases of lungs, followed by bilateral pleural effusions.
1
University of Texas Southwestern Medical Center, Dallas, Texas The Johns Hopkins Hospital, Baltimore, Maryland Dr Maryam Sayah is an adjunct instructor. Dr Christopher VandenBussche is an assistant professor. Dr Zahra Maleki is an assistant professor. The authors have no financial interest or conflicts of interest to disclose. *Correspondence to: Z. Maleki, MD, Assistant Professor of Pathology, The Johns Hopkins Hospital, Department of Pathology/Division of Cytology, 600 N. Wolfe Street/Carnegie 469C, Baltimore, MD 21287, USA. E-mail: [email protected] Received 4 March 2015; Revised 29 April 2015; Accepted 22 June 2015 DOI: 10.1002/dc.23315 Published online 17 July 2015 in Wiley Online Library (wileyonlinelibrary.com). 2
C 2015 WILEY PERIODICALS, INC. V
MD, PhD,
2
Case Report A 20-year-old female presented with severe right upper quadrant pain, nausea, and vomiting. Physical examination and laboratory findings were otherwise unremarkable. An MRI of the abdomen showed four lesions in the right lobe of the liver ranging from 1.2 to 3 cm in size. A subsequent percutaneous liver biopsy revealed EHE. Her work up also included CT of thorax, which revealed small nodular densities approximately 8 mm in diameter at the bases of lungs, most consistent with metastatic disease. She underwent chemoembolization; however, further subsequent imaging studies showed that her lesions were unchanged in size. One year later, the patient’s MRI revealed an increase in the size of the lung lesions with several new satellite lesions. She underwent additional chemoembolization and her disease remained stable for 9 years. After this period of time, she developed a large left pleural effusion with near-total consolidation of the lung plus multiple expansile metastases involving the eighth rib. Three months later, she was admitted for worsening dyspnea at both rest and with minimal exertion. A chest CT showed a left hydropneumothorax and small right pleural effusion. A left-sided pleural tube was placed which initially drained 200 cc of fluid. This fluid was sent to the cytopathology laboratory for analysis. Three slides were prepared including two cytospins and one cell block which subsequently stained with Papanicolaou stain and H&E, respectively. The Pap stain slides showed numerous neoplastic cells in clusters or individually in a background of lymphocytes and mesothelial cells. The neoplastic cells were intermediate to large as compared to mesothelial cells. The cells had high nuclear-to-cytoplasmic ratio. The nuclei were centrally located and they exhibited coarse granular chromatin, one or two nucleoli, and irregular nuclear membrane (Table I). Binucleation, multinucleation, and mitotic figures were common findings. Occasional nuclear grooves were noted while no cytoplasmic intranuclear pseudoinclusions were seen. Scattered plasmacytoid cells with eccentric nuclei Diagnostic Cytopathology, Vol. 43, No 9
751
Diagnostic Cytopathology DOI 10.1002/dc
SAYAH ET AL.
were present. The cytoplasm varied from medium to abundant and from relatively dense to vacuolated. Intracytoplasmic lumina containing red blood cells were found in scattered cells (Figs. 1 and 2) and were more easily recognizable on H&E slide of a cell block (Fig. 3). The tumor cells were immunoreactive for vascular markers including CD31 (Fig. 4), CD34 (Fig. 5), factor VIII (Fig. 6), and ERG vascular (Fig. 7) while they were nonreactive for BerEP4 and calretinin. Follow-up of the patient revealed that she died 15 months after developing persistent pleural effusion.
Table I. Cytomorphologic Findings of Epitheliod Hemangioendothelioma in Pleural Effusion Criteria
Pleural effusion
Cellularity Cellular arrangement Cellular shape Cellular size Cytoplasmic detail
Nuclear detail
background
Hypercellular Clusters and individual cells
Fig. 2. The tumor cells exhibit marked nuclear atypia. Binucleation, multinucleation, nuclear grooves, and a cell with an intracytoplasmic lumen containing red blood cells are noted (Papanicolaou stain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Round to oval, scattered plasmacytoid cells Intermediate to large Medium to abundant cytoplasm, relatively dense to vacuolated cytoplasm, occasional intracytoplasmic lumen containing red blood cells Centrally or eccentrically located nuclei containing coarse granular chromatin, one or two nucleoli, and irregular nuclear membrane, occasional nuclear grooves Common findings were binucleation, multinucleation, high nuclear to cytoplasmic ratio, and mitotic figures Lymhpocytes and mesothelial cells
Fig. 3. The tumor cells are much larger than mesothelial cells in the background. Note the gigantic cell with a large cytoplasmic lumen, which mimics a signet ring cell of an adenocarcinoma (H&E stain 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Discussion
Fig. 1. The tumor cells are seen individually and in clusters. Note: their high nuclear-to-cytoplasmic ratio, and occasional plasmacytoid cells (Papanicolaou stain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
752
Diagnostic Cytopathology, Vol. 43, No 9
EHE was first described in the lung as “intravascular bronchioloalveolar tumor”.2 EHE theoretically can arise in any site in the body, but most commonly occurs in the liver, bone, soft tissue, and lung.3 EHE mainly affects middle-aged adults but it can occur over a broad age range from 7 to 76 years.4 Despite being considered by some as a low-tointermediate-grade malignancy, the clinical course of the disease is unpredictable with the life expectancy ranging from 1 to 15 years. The highest mortality rate is 65% for patients with lung involvement.5,6
Diagnostic Cytopathology DOI 10.1002/dc
EHE IN PLEURAL EFFUSION
Fig. 4. The tumor cells are immunoreactive for CD31 (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 6. The tumor cells are immunoreactive for factor VIII (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. The tumor cells are immunoreactive for CD34 (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 7. The tumor cells are immunoreactive for vascular ERG displaying nuclear staining (immunostain 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The recurrence rate for this malignancy is approximately 10%. The rate of metastasis has been reported to be from 20% to 50.5%.1,5,7 The most common metastatic sites include the liver (22.6%), pleura (20.4%), and lymph nodes (10.8%).7 Pleural EHE is most commonly seen in older men who are symptomatic at presentation.8 The clinical symptoms include cough, chest pain, dyspnea, and weight loss. This is in contrast to EHE involving the lung parenchyma, which is more typically asymptomatic at diagnosis and discovered incidentally in middle-aged women.2,4 Poor prognostic factors include the presence of respiratory symptoms at presentation, lymphatic spread, pleural invasion, extensive intravascular spread, hepatic metasta-
ses, pleural effusion, fibrous pleuritis with extrapleural proliferation of tumor cells, and spindle tumor cells.2,4 Amin et al. observed some poor prognostic factors such as male sex, symptomatic presentation (the presence of cough, hemoptysis, and/or chest pain), multiple unilateral nodules, pleural effusion, and metastasis to more than one site. Metastasis to lymph nodes was also found to be a poor prognostic factor. The presence of symptoms upon presentation and presence of a pleural effusion were found to be independent predictors of survival in patients with pulmonary EHE.7 In a study by Bagan et al., the prognosis of pulmonary EHE was dependent on hemorrhagic symptoms (alveolar hemorrhage and/or hemoptysis), pleural effusion, and anemia. The reported 5-year survival of patients with a Diagnostic Cytopathology, Vol. 43, No 9
753
Diagnostic Cytopathology DOI 10.1002/dc
SAYAH ET AL.
pleural effusion was 2% while the survival of patients without an effusion was 73%.9 The radiological features of pleural EHE include smooth or nodular pleural thickening and pleural effusion. Macroscopically, the tumor forms a rind around the lung that may extend into the lung parenchyma along fissures and interlobular septa. Microscopically, the tumor grows as tubulopapillary structures and solid nests of epithelioid or histiocytoid cells in a myxoid or hyalinized stroma.8 The cytology of the pleural fluid specimen shows large plasmacytoid malignant cells in cohesive tissue fragments. The plasmacytoid cells have round, eccentrically located nuclei, intranuclear pseudoinclusions (INPI) and nuclear grooves. The tumor cells contain an abundant amount of cytoplasm with distinct boarders and high nuclear cytoplasmic ratios.3 Buggage et al. reported similar findings to ours as a case report. However, they did not report nuclear grooves. Murali et al. reported nuclear grooves and INPI with occasional intraluminal red blood cells, which were similar to our findings.5 The cytoplasm is eosinophilic, dense, and granularappearing with single or multiple vacuoles and intracytoplasmic lumina (ICL). Erythrocytes or fragments of erythrocyte cytoplasm may be identified within ICL.5 Enbom et al. reported a case of EHE in ascitic fluid and they described the neoplastic cells as relatively bland and often obscured by reactive mesothelial cells,10 which is in contrary with our findings, as well as Buggage’s et al. and Murali’s et al.3,5 The diagnosis of EHE is confirmed by using immunohistochemical staining such as Factor VIII, CD34, and CD31.8 Electron microscopy shows Weibel–Palade bodies (fine grid-like structures), which are very characteristic of EHE. Other malignancies involving the pleura including adenocarcinoma, mesothelioma, melanoma, and neuroendocrine tumors should be considered in the differential diagnosis of pleural EHE due to similarity of these tumors on the radiologic appearance and the relative rarity of EHE. Among carcinomas, renal cell carcinoma, hepatocellular carcinoma, and adrenocortical carcinoma should be included.3 Large plasmacytoid vacuolated cells of EHE may mimic signet ring cell carcinoma11 or even sarcoma.12 Distinguishing adenocarcinoma from EHE is difficult by fine-needle aspiration smears alone. EHE and adenocarcinoma have several overlapping cytology features such as three-dimensional cellular aggregates, cytoplasmic vacuoles, and the presence of nucleoli. However, the presence of scant, foamy cytoplasm and conspicuous nucleoli is more compatible with adenocarcinoma. Adenocarcinoma is positive for CEA, Leu M1, and HMFG-2.5,13,14 The fine-needle aspiration biopsy of malignant mesothelioma may contain epithelioid cell clusters with little atypia and papillary formation like EHE. However, meso754
Diagnostic Cytopathology, Vol. 43, No 9
thelioma typically has fading cytoplasmic borders and intercellular spaces, and lack of cytoplasmic vacuoles. Differentiating mesothelioma from pleural EHE generally requires immunoperoxidase staining. Malignant mesothelioma is negative for endothelial markers such as CD31 and CD34. The expression of epithelial markers, mesenchymal markers, and mesothelial cell markers is seen in mesothelioma. Mesothelioma is positive for CK, CK7, CK5/6, vimentin, calretinin, and WT-1.5,15,16 However, EHE can sometimes express keratins. Moreover, distinguishing EHE from epithelioid angiosarcoma (EAS) is also challenging. EAS is an aggressive vascular malignancy, which can occur in similar sites as EHE such as bone, lung, liver, and soft tissue. EAS is more common in males with the highest incidence in the seventh decade of life. Both EAS and EHE lesions have epithelioid morphology and immunohistochemistry of these two entities overlapping. Common features include epithelioid morphology, eccentrically placed nucleus and intracytoplasmic lumens. Although greater cellularity, large cells, prominent nucleoli, and nuclear pleomorphism may favor EAS, the presence of nuclear grooves appears to be more specific for EHE.5,6,17 Because the two entities can share similar immunoprofiles, a definitive diagnosis of EHE vs. EAS typically requires examination of architecture on core biopsy material. The treatment of EHE depends on their localization. In limited pulmonary or hepatic forms, surgical excision is the treatment of choice. However, pleural EHE surgical resection is often impossible due to advanced disease.8,18,19 Dail et al. have recommended follow-up and no therapy in asymptomatic patients.2 Kitaichi et al. reported three cases of spontaneous regression.4 Different chemotherapeutic regimens have been used such as carboplatin, etoposide, bevacizumab, interferon-2a, and azathioprine in attempts to stop or slow progression of EHE.13,18,20,21 Pinet et al. reported the complete remission of pleural EHE with carboplatin and etoposide.22 In conclusion, diagnosis of EHE can be challenging. Awareness of this entity and other neoplasms in its differential diagnosis, careful examination of the cytolomorphological features, and characteristic immunohistochemical profile of EHE are important keys to reach an accurate diagnosis.
References 1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: A vascular tumor often mistaken for a carcinoma. Cancer 1982; 50: 970–981. 2. Dail DH, Liebow AA. Intravascular bronchioloalveolar tumor (Abstract). Am J Pathol 1975; 78:6a–7a. 3. Buggage RR, Soudi N, Olson JL, Busseniers AE. Epithelioid hemangioendothelioma of the lung: Pleural effusion cytology, ultrastructure, and brief literature review. Diagn Cytopathol 1995; 13: 54–60.
Diagnostic Cytopathology DOI 10.1002/dc
EHE IN PLEURAL EFFUSION 4. Kitaichi M, Nagai S, Nishimura K, et al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. Eur Respir J 1998; 12:89–96. 5. Murali R, Zarka MA, Ocal IT, Tazelaar HD. Cytologic features of epithelioid hemangioendothelioma. Am J Clin Pathol 2011; 136: 739–746. 6. VandenBussche CJ, Wakely PE, Jr., Siddiqui MT, Maleki Z, Ali SZ. Cytopathologic characteristics of epithelioid vascular malignancies. Acta Cytol 2014; 58:356–366. 7. 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. 8. Crotty EJ, McAdams HP, Erasmus JJ, Sporn TA, Roggli VL. Epithelioid hemangioendothelioma of the pleura: Clinical and radiologic features. AJR Am J Roentgenol 2000; 175:1545–1549. 9. Bagan P, Hassan M, Le Pimpec Barthes F, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: A review of the literature. Ann Thorac Surg 2006; 82:2010–2013. 10. Enbom ET, Abasolo PA, Dixon JR, Nikolaenko LM, French SW, Duane GB. Cytomorphological features of epithelioid hemangioendothelioma in ascitic fluid with radiological, clinical and histopathological correlations. Acta Cytol 2014; 58:211–216. 11. Hristova EN, Krishnamurthy S, Ro JY Ayala AG. Pulmonary epithelioid hemangioendothelioma with prominent signet ring cell features mimicking metastatic adenocarcinoma. Ann Diagn Pathol 2003; 7:160–164. 12. Tong GX, Hamele-Bena D, Borczuk A, Monaco S, Khosh MM Greenebaum E. Fine needle aspiration biopsy of epithelioid hemangioendothelioma of the oral cavity: Report of one case and review of literature. Diagn Cytopathol 2006; 34:218–223.
13. Ryu HS, Lee SS, Choi HS, Baek H, Koh JS. A case of pulmonary malignant epithelioid hemangioendothelioma misdiagnosed as adenocarcinoma by fine needle aspiration cytology. Diagn Cytopathol 2011; 39:801–807. 14. Sheibani K, Battifora H, Burke JS. Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas. An immunohistologic analysis demonstrating the value of Leu M1 antigen. Am J Pathol 1986; 123:212–219. 15. Saqi A, Nisbet L, Gagneja P, Leslie KO. Primary pleural epithelioid hemangioendothelioma with rhabdoid phenotype: Report and review of the literature. Diagn Cytopathol 2007; 35:203–208. 16. Shao J, Zhang J. Clinicopathological characteristics of pulmonary epithelioid hemangioendothelioma: A report of four cases and review of the literature. Oncol Lett 2014; 8:2517–2522. 17. Hart J, Mandavilli S. Epithelioid angiosarcoma: A brief diagnostic review and differential diagnosis. Arch Pathol Lab Med 2011; 135: 268–272. 18. Lee YJ, Chung MJ, Jeong KC, et al. Pleural epithelioid hemangioendothelioma. Yonsei Med J 2008; 49:1036–1040. 19. Lazarus A, Fuhrer G, Malekiani C, McKay S, Thurber J. Primary pleural epithelioid hemangioendothelioma (EHE)–two cases and review of the literature. Clin Respir J 2011; 5:e1–e5. 20. Roudier-Pujol C, Enjolras O, Lacronique J, et al. Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment. Ann Dermatol Venereol 1994; 121: 898–904. 21. Ledson MJ, Convery R, Carty A, Evans CC. Epithelioid haemangioendothelioma. Thorax 1999; 54:560–561. 22. Pinet C, Magnan A, Garbe L, Payan MJ, Vervloet D. Aggressive form of pleural epithelioid haemangioendothelioma: Complete response after chemotherapy. Eur Respir J 1999; 14:237–238.
Diagnostic Cytopathology, Vol. 43, No 9
755
Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin with variable morphological features and unpredictable biological behavior. EHE occasionally involves the pleural fluid. However, the cytomorphology of EHE found in pleural fluid has not been well characterized in the literature. Herein we describe a case of EHE, initially presenting as multiple liver lesions plus several small nodular densities at the bases of the lungs followed by bilateral pleural effusions. C 2015 Wiley Periodicals, Diagn. Cytopathol. 2015;43:751–755. V Inc. Key Words: pleural effusion; cytology; epithelioid hemangioendothelioma; vascular neoplasm
Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin with variable morphological features and unpredictable biological behavior. In 1982, EHE was first described by Weiss and Enzinger as a low-grade angiosarcoma.1 While these lesions are sometimes diagnosed on the fine-needle aspiration of a solid lesion, EHE occasionally involves the pleural fluid. However, the cytomorphology of EHE found in pleural fluid has not been well characterized in literature. Here we describe a case of EHE, initially presenting as multiple liver lesions plus several small nodular densities at the bases of lungs, followed by bilateral pleural effusions.
1
University of Texas Southwestern Medical Center, Dallas, Texas The Johns Hopkins Hospital, Baltimore, Maryland Dr Maryam Sayah is an adjunct instructor. Dr Christopher VandenBussche is an assistant professor. Dr Zahra Maleki is an assistant professor. The authors have no financial interest or conflicts of interest to disclose. *Correspondence to: Z. Maleki, MD, Assistant Professor of Pathology, The Johns Hopkins Hospital, Department of Pathology/Division of Cytology, 600 N. Wolfe Street/Carnegie 469C, Baltimore, MD 21287, USA. E-mail: [email protected] Received 4 March 2015; Revised 29 April 2015; Accepted 22 June 2015 DOI: 10.1002/dc.23315 Published online 17 July 2015 in Wiley Online Library (wileyonlinelibrary.com). 2
C 2015 WILEY PERIODICALS, INC. V
MD, PhD,
2
Case Report A 20-year-old female presented with severe right upper quadrant pain, nausea, and vomiting. Physical examination and laboratory findings were otherwise unremarkable. An MRI of the abdomen showed four lesions in the right lobe of the liver ranging from 1.2 to 3 cm in size. A subsequent percutaneous liver biopsy revealed EHE. Her work up also included CT of thorax, which revealed small nodular densities approximately 8 mm in diameter at the bases of lungs, most consistent with metastatic disease. She underwent chemoembolization; however, further subsequent imaging studies showed that her lesions were unchanged in size. One year later, the patient’s MRI revealed an increase in the size of the lung lesions with several new satellite lesions. She underwent additional chemoembolization and her disease remained stable for 9 years. After this period of time, she developed a large left pleural effusion with near-total consolidation of the lung plus multiple expansile metastases involving the eighth rib. Three months later, she was admitted for worsening dyspnea at both rest and with minimal exertion. A chest CT showed a left hydropneumothorax and small right pleural effusion. A left-sided pleural tube was placed which initially drained 200 cc of fluid. This fluid was sent to the cytopathology laboratory for analysis. Three slides were prepared including two cytospins and one cell block which subsequently stained with Papanicolaou stain and H&E, respectively. The Pap stain slides showed numerous neoplastic cells in clusters or individually in a background of lymphocytes and mesothelial cells. The neoplastic cells were intermediate to large as compared to mesothelial cells. The cells had high nuclear-to-cytoplasmic ratio. The nuclei were centrally located and they exhibited coarse granular chromatin, one or two nucleoli, and irregular nuclear membrane (Table I). Binucleation, multinucleation, and mitotic figures were common findings. Occasional nuclear grooves were noted while no cytoplasmic intranuclear pseudoinclusions were seen. Scattered plasmacytoid cells with eccentric nuclei Diagnostic Cytopathology, Vol. 43, No 9
751
Diagnostic Cytopathology DOI 10.1002/dc
SAYAH ET AL.
were present. The cytoplasm varied from medium to abundant and from relatively dense to vacuolated. Intracytoplasmic lumina containing red blood cells were found in scattered cells (Figs. 1 and 2) and were more easily recognizable on H&E slide of a cell block (Fig. 3). The tumor cells were immunoreactive for vascular markers including CD31 (Fig. 4), CD34 (Fig. 5), factor VIII (Fig. 6), and ERG vascular (Fig. 7) while they were nonreactive for BerEP4 and calretinin. Follow-up of the patient revealed that she died 15 months after developing persistent pleural effusion.
Table I. Cytomorphologic Findings of Epitheliod Hemangioendothelioma in Pleural Effusion Criteria
Pleural effusion
Cellularity Cellular arrangement Cellular shape Cellular size Cytoplasmic detail
Nuclear detail
background
Hypercellular Clusters and individual cells
Fig. 2. The tumor cells exhibit marked nuclear atypia. Binucleation, multinucleation, nuclear grooves, and a cell with an intracytoplasmic lumen containing red blood cells are noted (Papanicolaou stain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Round to oval, scattered plasmacytoid cells Intermediate to large Medium to abundant cytoplasm, relatively dense to vacuolated cytoplasm, occasional intracytoplasmic lumen containing red blood cells Centrally or eccentrically located nuclei containing coarse granular chromatin, one or two nucleoli, and irregular nuclear membrane, occasional nuclear grooves Common findings were binucleation, multinucleation, high nuclear to cytoplasmic ratio, and mitotic figures Lymhpocytes and mesothelial cells
Fig. 3. The tumor cells are much larger than mesothelial cells in the background. Note the gigantic cell with a large cytoplasmic lumen, which mimics a signet ring cell of an adenocarcinoma (H&E stain 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Discussion
Fig. 1. The tumor cells are seen individually and in clusters. Note: their high nuclear-to-cytoplasmic ratio, and occasional plasmacytoid cells (Papanicolaou stain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
752
Diagnostic Cytopathology, Vol. 43, No 9
EHE was first described in the lung as “intravascular bronchioloalveolar tumor”.2 EHE theoretically can arise in any site in the body, but most commonly occurs in the liver, bone, soft tissue, and lung.3 EHE mainly affects middle-aged adults but it can occur over a broad age range from 7 to 76 years.4 Despite being considered by some as a low-tointermediate-grade malignancy, the clinical course of the disease is unpredictable with the life expectancy ranging from 1 to 15 years. The highest mortality rate is 65% for patients with lung involvement.5,6
Diagnostic Cytopathology DOI 10.1002/dc
EHE IN PLEURAL EFFUSION
Fig. 4. The tumor cells are immunoreactive for CD31 (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 6. The tumor cells are immunoreactive for factor VIII (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. The tumor cells are immunoreactive for CD34 (immunostain 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 7. The tumor cells are immunoreactive for vascular ERG displaying nuclear staining (immunostain 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The recurrence rate for this malignancy is approximately 10%. The rate of metastasis has been reported to be from 20% to 50.5%.1,5,7 The most common metastatic sites include the liver (22.6%), pleura (20.4%), and lymph nodes (10.8%).7 Pleural EHE is most commonly seen in older men who are symptomatic at presentation.8 The clinical symptoms include cough, chest pain, dyspnea, and weight loss. This is in contrast to EHE involving the lung parenchyma, which is more typically asymptomatic at diagnosis and discovered incidentally in middle-aged women.2,4 Poor prognostic factors include the presence of respiratory symptoms at presentation, lymphatic spread, pleural invasion, extensive intravascular spread, hepatic metasta-
ses, pleural effusion, fibrous pleuritis with extrapleural proliferation of tumor cells, and spindle tumor cells.2,4 Amin et al. observed some poor prognostic factors such as male sex, symptomatic presentation (the presence of cough, hemoptysis, and/or chest pain), multiple unilateral nodules, pleural effusion, and metastasis to more than one site. Metastasis to lymph nodes was also found to be a poor prognostic factor. The presence of symptoms upon presentation and presence of a pleural effusion were found to be independent predictors of survival in patients with pulmonary EHE.7 In a study by Bagan et al., the prognosis of pulmonary EHE was dependent on hemorrhagic symptoms (alveolar hemorrhage and/or hemoptysis), pleural effusion, and anemia. The reported 5-year survival of patients with a Diagnostic Cytopathology, Vol. 43, No 9
753
Diagnostic Cytopathology DOI 10.1002/dc
SAYAH ET AL.
pleural effusion was 2% while the survival of patients without an effusion was 73%.9 The radiological features of pleural EHE include smooth or nodular pleural thickening and pleural effusion. Macroscopically, the tumor forms a rind around the lung that may extend into the lung parenchyma along fissures and interlobular septa. Microscopically, the tumor grows as tubulopapillary structures and solid nests of epithelioid or histiocytoid cells in a myxoid or hyalinized stroma.8 The cytology of the pleural fluid specimen shows large plasmacytoid malignant cells in cohesive tissue fragments. The plasmacytoid cells have round, eccentrically located nuclei, intranuclear pseudoinclusions (INPI) and nuclear grooves. The tumor cells contain an abundant amount of cytoplasm with distinct boarders and high nuclear cytoplasmic ratios.3 Buggage et al. reported similar findings to ours as a case report. However, they did not report nuclear grooves. Murali et al. reported nuclear grooves and INPI with occasional intraluminal red blood cells, which were similar to our findings.5 The cytoplasm is eosinophilic, dense, and granularappearing with single or multiple vacuoles and intracytoplasmic lumina (ICL). Erythrocytes or fragments of erythrocyte cytoplasm may be identified within ICL.5 Enbom et al. reported a case of EHE in ascitic fluid and they described the neoplastic cells as relatively bland and often obscured by reactive mesothelial cells,10 which is in contrary with our findings, as well as Buggage’s et al. and Murali’s et al.3,5 The diagnosis of EHE is confirmed by using immunohistochemical staining such as Factor VIII, CD34, and CD31.8 Electron microscopy shows Weibel–Palade bodies (fine grid-like structures), which are very characteristic of EHE. Other malignancies involving the pleura including adenocarcinoma, mesothelioma, melanoma, and neuroendocrine tumors should be considered in the differential diagnosis of pleural EHE due to similarity of these tumors on the radiologic appearance and the relative rarity of EHE. Among carcinomas, renal cell carcinoma, hepatocellular carcinoma, and adrenocortical carcinoma should be included.3 Large plasmacytoid vacuolated cells of EHE may mimic signet ring cell carcinoma11 or even sarcoma.12 Distinguishing adenocarcinoma from EHE is difficult by fine-needle aspiration smears alone. EHE and adenocarcinoma have several overlapping cytology features such as three-dimensional cellular aggregates, cytoplasmic vacuoles, and the presence of nucleoli. However, the presence of scant, foamy cytoplasm and conspicuous nucleoli is more compatible with adenocarcinoma. Adenocarcinoma is positive for CEA, Leu M1, and HMFG-2.5,13,14 The fine-needle aspiration biopsy of malignant mesothelioma may contain epithelioid cell clusters with little atypia and papillary formation like EHE. However, meso754
Diagnostic Cytopathology, Vol. 43, No 9
thelioma typically has fading cytoplasmic borders and intercellular spaces, and lack of cytoplasmic vacuoles. Differentiating mesothelioma from pleural EHE generally requires immunoperoxidase staining. Malignant mesothelioma is negative for endothelial markers such as CD31 and CD34. The expression of epithelial markers, mesenchymal markers, and mesothelial cell markers is seen in mesothelioma. Mesothelioma is positive for CK, CK7, CK5/6, vimentin, calretinin, and WT-1.5,15,16 However, EHE can sometimes express keratins. Moreover, distinguishing EHE from epithelioid angiosarcoma (EAS) is also challenging. EAS is an aggressive vascular malignancy, which can occur in similar sites as EHE such as bone, lung, liver, and soft tissue. EAS is more common in males with the highest incidence in the seventh decade of life. Both EAS and EHE lesions have epithelioid morphology and immunohistochemistry of these two entities overlapping. Common features include epithelioid morphology, eccentrically placed nucleus and intracytoplasmic lumens. Although greater cellularity, large cells, prominent nucleoli, and nuclear pleomorphism may favor EAS, the presence of nuclear grooves appears to be more specific for EHE.5,6,17 Because the two entities can share similar immunoprofiles, a definitive diagnosis of EHE vs. EAS typically requires examination of architecture on core biopsy material. The treatment of EHE depends on their localization. In limited pulmonary or hepatic forms, surgical excision is the treatment of choice. However, pleural EHE surgical resection is often impossible due to advanced disease.8,18,19 Dail et al. have recommended follow-up and no therapy in asymptomatic patients.2 Kitaichi et al. reported three cases of spontaneous regression.4 Different chemotherapeutic regimens have been used such as carboplatin, etoposide, bevacizumab, interferon-2a, and azathioprine in attempts to stop or slow progression of EHE.13,18,20,21 Pinet et al. reported the complete remission of pleural EHE with carboplatin and etoposide.22 In conclusion, diagnosis of EHE can be challenging. Awareness of this entity and other neoplasms in its differential diagnosis, careful examination of the cytolomorphological features, and characteristic immunohistochemical profile of EHE are important keys to reach an accurate diagnosis.
References 1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: A vascular tumor often mistaken for a carcinoma. Cancer 1982; 50: 970–981. 2. Dail DH, Liebow AA. Intravascular bronchioloalveolar tumor (Abstract). Am J Pathol 1975; 78:6a–7a. 3. Buggage RR, Soudi N, Olson JL, Busseniers AE. Epithelioid hemangioendothelioma of the lung: Pleural effusion cytology, ultrastructure, and brief literature review. Diagn Cytopathol 1995; 13: 54–60.
Diagnostic Cytopathology DOI 10.1002/dc
EHE IN PLEURAL EFFUSION 4. Kitaichi M, Nagai S, Nishimura K, et al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. Eur Respir J 1998; 12:89–96. 5. Murali R, Zarka MA, Ocal IT, Tazelaar HD. Cytologic features of epithelioid hemangioendothelioma. Am J Clin Pathol 2011; 136: 739–746. 6. VandenBussche CJ, Wakely PE, Jr., Siddiqui MT, Maleki Z, Ali SZ. Cytopathologic characteristics of epithelioid vascular malignancies. Acta Cytol 2014; 58:356–366. 7. 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. 8. Crotty EJ, McAdams HP, Erasmus JJ, Sporn TA, Roggli VL. Epithelioid hemangioendothelioma of the pleura: Clinical and radiologic features. AJR Am J Roentgenol 2000; 175:1545–1549. 9. Bagan P, Hassan M, Le Pimpec Barthes F, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: A review of the literature. Ann Thorac Surg 2006; 82:2010–2013. 10. Enbom ET, Abasolo PA, Dixon JR, Nikolaenko LM, French SW, Duane GB. Cytomorphological features of epithelioid hemangioendothelioma in ascitic fluid with radiological, clinical and histopathological correlations. Acta Cytol 2014; 58:211–216. 11. Hristova EN, Krishnamurthy S, Ro JY Ayala AG. Pulmonary epithelioid hemangioendothelioma with prominent signet ring cell features mimicking metastatic adenocarcinoma. Ann Diagn Pathol 2003; 7:160–164. 12. Tong GX, Hamele-Bena D, Borczuk A, Monaco S, Khosh MM Greenebaum E. Fine needle aspiration biopsy of epithelioid hemangioendothelioma of the oral cavity: Report of one case and review of literature. Diagn Cytopathol 2006; 34:218–223.
13. Ryu HS, Lee SS, Choi HS, Baek H, Koh JS. A case of pulmonary malignant epithelioid hemangioendothelioma misdiagnosed as adenocarcinoma by fine needle aspiration cytology. Diagn Cytopathol 2011; 39:801–807. 14. Sheibani K, Battifora H, Burke JS. Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas. An immunohistologic analysis demonstrating the value of Leu M1 antigen. Am J Pathol 1986; 123:212–219. 15. Saqi A, Nisbet L, Gagneja P, Leslie KO. Primary pleural epithelioid hemangioendothelioma with rhabdoid phenotype: Report and review of the literature. Diagn Cytopathol 2007; 35:203–208. 16. Shao J, Zhang J. Clinicopathological characteristics of pulmonary epithelioid hemangioendothelioma: A report of four cases and review of the literature. Oncol Lett 2014; 8:2517–2522. 17. Hart J, Mandavilli S. Epithelioid angiosarcoma: A brief diagnostic review and differential diagnosis. Arch Pathol Lab Med 2011; 135: 268–272. 18. Lee YJ, Chung MJ, Jeong KC, et al. Pleural epithelioid hemangioendothelioma. Yonsei Med J 2008; 49:1036–1040. 19. Lazarus A, Fuhrer G, Malekiani C, McKay S, Thurber J. Primary pleural epithelioid hemangioendothelioma (EHE)–two cases and review of the literature. Clin Respir J 2011; 5:e1–e5. 20. Roudier-Pujol C, Enjolras O, Lacronique J, et al. Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment. Ann Dermatol Venereol 1994; 121: 898–904. 21. Ledson MJ, Convery R, Carty A, Evans CC. Epithelioid haemangioendothelioma. Thorax 1999; 54:560–561. 22. Pinet C, Magnan A, Garbe L, Payan MJ, Vervloet D. Aggressive form of pleural epithelioid haemangioendothelioma: Complete response after chemotherapy. Eur Respir J 1999; 14:237–238.
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