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A 30-Year-Old Man With Facial Flushing and a Mediastinal Mass
CHEST
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
A 30-Year-Old Man With Facial Flushing and a Mediastinal Mass Jonathan Ohebsion, MD; William N. O’Connor, MD; Anil K. Attili, MD; and Enrique Diaz-Guzman, MD
CHEST 2010; 138(3 ):746–749
A
30-year-old man presented to the ED complaining of recurrent episodes of facial flushing, described as a “sensation of fullness and redness” in his face when adopting the supine position. These symptoms started 2 months prior to presentation and were associated with headache, orthopnea, chest pain, and nonproductive cough. The patient denied any history of recent respiratory illness, diarrhea, dyspnea, weight loss, fever, diaphoresis, skin rash, dizziness, or hoarseness. His past medical history was significant for psoriasis and a right inguinal hernia repair. Social history included tobacco abuse (one pack per day for 10 years). He reported a history of lymphoma in two members of his family. The patient denied use of any medications. Physical Examination On hospital admission, the patient’s temperature was 36°C, BP was 149Ⲑ99 mm Hg, heart rate was 91 beatsⲐmin, respiratory rate was 16 breathsⲐmin, and oxygen saturation was 100% on room air. A head and neck examination demonstrated bilateral neck vein distention and facial flushing when the patient was placed in the supine position. There was no palpable mass, lymphadenopathy, or thyromegaly. The lungs were clear to auscultation. A heart examination Manuscript received November 30, 2009; revision accepted February 6, 2010. Affiliations: From the Department of Internal Medicine (Dr Ohebsion); the Department of Pathology and Laboratory Medicine (Dr O’Connor); the Department of Radiology (Dr Attili); and the Department of Pulmonary and Critical Care (Dr Diaz-Guzman), University of Kentucky, Lexington, KY. Correspondence to: Enrique Diaz-Guzman, MD, University of Kentucky, 740 S Limestone St, L543 Kentucky Clinic, Lexington, KY 40536-0284; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378Ⲑchest.09-2847 746
showed muffled heart sounds without murmurs or gallops. Laboratory and Radiographic Findings Blood testing showed a hemoglobin concentration of 11.7 gⲐdL. Renal function, electrolyte and calcium levels, liver panel, and coagulation times were unremarkable. An ECG showed a normal sinus rhythm at a rate of 83 beatsⲐmin and normal axis. A plain chest radiograph showed cardiomegaly without pulmonary congestion or pleural effusions. An echocardiogram revealed the presence of a large circumferential pericardial effusion. The patient underwent a pericardiocentesis with a pigtail catheter insertion, which drained 1.6 L of bloody fluid. Cytologic examination of the pericardial fluid showed the presence of epithelioid cells, but was negative for malignancy. A gram stain showed numerous RBCs but no organisms. The results of cultures and special stains were negative. A CT scan of the chest after pericardiocentesis revealed the presence of a mediastinal mass (Figs 1, 2).
Figure 1. Axial CT scan section with IV contrast showing a soft tissue mass (asterisk) in the precarinal region extending inferiorly into the pericardial recess between the right pulmonary artery (arrow) and the ascending aorta (arrow head). Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
Figure 2. Axial CT scan section showing the mass (asterisk) in relation to the SVC (arrow). SVC 5 superior vena cava.
The patient was taken to the bronchoscopy suite for an airway examination and transbronchial needle aspiration of the mediastinal mass. Approximately five samples from the mass were obtained using a No. 21 cytology needle. Fine-needle aspirates were used to review for the presence of atypical epithelioid cells in a background of reactive bronchial epithelium, but no evidence of atypical lymphocytes or malignant cells was observed (specimen not shown). A mediastinoscopy was subsequently performed, obtaining multiple biopsy specimens from the mass (Fig 3).
www.chestpubs.org
Figure 3. High-power light micrograph of mediastinal biopsy tissue immunostained for the endothelial cell marker CD31, showing individual vacuolated malignant tumor cells with strong membrane positivity (original magnification 320).
What is the diagnosis?
CHEST / 138 / 3 / SEPTEMBER, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
747
Diagnosis: Epithelioid hemangioendothelioma of the anterior mediastinum
Discussion Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin, characterized by the presence of endothelial cells with primitive vascular differentiation, frequently described as having an epithelioid or histiocytoid appearance. Initially reported as an intravascular bronchioloalveolar tumor with a propensity for vascular invasion, EHE demonstrates histologic and clinical features intermediate between those of benign hemangioma and angiosarcoma. Because of the presence of epithelioid and histiocytoid cells, this malignancy has been confused with metastatic carcinoma, granulomatous diseases, or Langerhans cell histiocytosis. EHE has been described affecting many sites of the body, including lung, liver, bone, brain, lymph nodes, and breast. When involving the chest, the tumor more commonly affects the lung parenchyma, although several cases of mediastinal involvement have also been described. Pulmonary EHE is rare, with a recent report suggesting , 100 cases described in the literature. This neoplasm frequently presents as an incidental finding because patients are often asymptomatic at the time of diagnosis. Pulmonary EHE appears to be more common in women, with patients ranging in age from 7 to 76 years, with a mean onset of 35 years. CT scans of the chest show multiple perivascular nodules that range in size up to 2 cm, but most are , 1 cm. Other possible findings include hilar lymph node enlargement (9%) and pleural effusions (10%). Mediastinal involvement with this tumor is possible. A review of the medical literature in 1994 reported only 34 cases of mediastinal EHE published. Approximately 17 more cases describing EHE arising from the mediastinum have been reported since then. All cases except one describe involvement of the anterior mediastinum. The clinical presentation of mediastinal EHE is indistinguishable from other mediastinal masses, and most cases are discovered incidentally because patients remain asymptomatic until the tumor expands to involve adjacent structures. Symptoms related to mediastinal involvement are nonspecific and include chest pain, cough, dyspnea, dysphagia, stridor, wheezing, vocal cord paralysis, and complaints suggestive of superior vena cava (SVC) obstruction. The diagnosis of this neoplasm can be challenging because the tumor can arise from many organ systems and it may be difficult to determine if it represents a metastasis or a primary lesion. Although cytologic 748
and morphologic features may be suggestive of an alternate diagnosis, confirmation of an EHE requires a tissue biopsy, and most of the pulmonary or mediastinal cases of thoracic EHE have been diagnosed after a thoracoscopic biopsy or resection of the mass. The diagnosis is based on a combination of pathologic findings and the presence of immunohistochemical features showing tumor expression positivity for endothelial cells (ie, CD31, CD34, thrombomodulin, and FLI-1). In addition, EHE can focally stain with S-100 and smooth muscle actin. Electron microscopic examination of an EHE shows a cohesive population of cells characterized by large nuclei, irregular clumping of chromatin, and nucleoli. The cells contain abundant cytoplasm and intracytoplasmic intermediate (vimentin) filaments. Certain atypical histologic features such as cellular pleomorphism and increased mitotic activity indicate the potential for malignant behavior. The prognosis of EHE is variable. Distant metastases are present in up to 50% of patients, with hepatic metastases being the most common, followed by pleural metastases and lymph node metastases. Factors associated with a poor prognosis include the presence of atypical histologic findings, large size of the tumor, presence of pleural effusion, and clinical symptoms suggestive of extensive vascular, pulmonary, or pleural involvement. Spontaneous regression in asymptomatic patients has been described, with many patients living up to 15 to 20 years after surgical excision of the tumor. A review of EHE involving soft tissues noted an overall local recurrence rate of 13% within 48 months and a mortality rate of 13%. Atypical histologic findings suggestive of malignant potential are associated with a metastasis rate of 53% and a death rate of 31%, while the absence of these features is associated with a much better prognosis. There is no standard treatment of EHE. Surgical excision, chemotherapy with carboplatin or cisplatin plus etoposide, and treatment with interferon-a2b have been reported successful to achieve partial or complete remission. Clinical Course In our patient, review of the CT scan of the chest (Fig 1) revealed a uniform soft tissue mass (asterisk) (35 Hounsfield units) in the precarinal region, extending from above the level of the aortic arch of the neck vessels inferiorly into the pericardial recess between the right pulmonary artery (arrow) and the ascending aorta (arrowhead). The mass (asterisk) measured approximately 4.8 3 5 cm at the level of the carina and extended into the pericardial recess between the aortic root and the SVC, located in close contact with the SVC (arrow), which was displaced Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
but patent (Fig 2). Because of the patient’s young age and family history, and the presence of a pericardial effusion, the initial diagnostic consideration was lymphoma. Nevertheless, the absence of lymphoid tissue in a transbronchial needle aspiration of the mass and the presence of epithelioid cells noted in the cytology examination suggested the possibility of an EHE. The patient underwent a diagnostic mediastinoscopy with biopsies. Pathologic examination showed a round, plump, clear-to-eosinophilic, moderately atypical tumor cell occupying a focally chondroid matrix, sometimes forming nests. Necrosis was present centripetally away from perivascular growth. Immunostains showed tumor cell positivity for CD31 (Fig 3) and thrombomodulin, and diffuse nuclear positivity for FLI-1. These finding were consistent with EHE. The patient was referred to an oncologist specialist who recommended radiation therapy and treatment with cisplatin. The patient initially improved after therapy, but a follow-up CT scan of the chest after 2 months revealed a significant increase in the size of the mass. Clinical Pearls 1. Because of its epithelioid nature, EHE can be confused with metastatic carcinoma. 2. Thoracic EHE affects the lung more commonly than the mediastinum. 3. The presence of cytologic features of epithelioid cells in a young patient with an anterior mediastinal mass must alert the clinician about the possibility of EHE. 4. The prognosis of EHE is variable, and surgical resection appears to be the only curative treatment,
www.chestpubs.org
although spontaneous regression of the tumor has been reported. Acknowledgments FinancialⲐnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesⲐorganizations whose products or services may be discussed in this article.
Suggested Readings Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970-981. Suster S, Moran CA, Koss MN. Epithelioid hemangioendothelioma of the anterior mediastinum. Clinicopathologic, immunohistochemical, and ultrastructural analysis of 12 cases. Am J Surg Pathol. 1994;18(9):871-881. Erasmus JJ, McAdams HP, Carraway MS. A 63-year-old woman with weight loss and multiple lung nodules. Chest. 1997;111(1):236-238. Fletcher CDM, Unni KK, Mertens F, et al. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002. Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125(2):789-793. 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. Campos J, Otero E, Dominguez MJ, Gonzalez-Quintela A. Epithelioid hemangioendothelioma in the posterior mediastinum. Eur J Intern Med. 2007;18(4):331-332. Antic T, Staerkel G. Mediastinal epithelioid hemangioendothelioma metastatic to lymph nodes and pleural fluid: report of a case. Diagn Cytopathol. 2009;38(2):113-116.
CHEST / 138 / 3 / SEPTEMBER, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
749
Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS
A 30-Year-Old Man With Facial Flushing and a Mediastinal Mass Jonathan Ohebsion, MD; William N. O’Connor, MD; Anil K. Attili, MD; and Enrique Diaz-Guzman, MD
CHEST 2010; 138(3 ):746–749
A
30-year-old man presented to the ED complaining of recurrent episodes of facial flushing, described as a “sensation of fullness and redness” in his face when adopting the supine position. These symptoms started 2 months prior to presentation and were associated with headache, orthopnea, chest pain, and nonproductive cough. The patient denied any history of recent respiratory illness, diarrhea, dyspnea, weight loss, fever, diaphoresis, skin rash, dizziness, or hoarseness. His past medical history was significant for psoriasis and a right inguinal hernia repair. Social history included tobacco abuse (one pack per day for 10 years). He reported a history of lymphoma in two members of his family. The patient denied use of any medications. Physical Examination On hospital admission, the patient’s temperature was 36°C, BP was 149Ⲑ99 mm Hg, heart rate was 91 beatsⲐmin, respiratory rate was 16 breathsⲐmin, and oxygen saturation was 100% on room air. A head and neck examination demonstrated bilateral neck vein distention and facial flushing when the patient was placed in the supine position. There was no palpable mass, lymphadenopathy, or thyromegaly. The lungs were clear to auscultation. A heart examination Manuscript received November 30, 2009; revision accepted February 6, 2010. Affiliations: From the Department of Internal Medicine (Dr Ohebsion); the Department of Pathology and Laboratory Medicine (Dr O’Connor); the Department of Radiology (Dr Attili); and the Department of Pulmonary and Critical Care (Dr Diaz-Guzman), University of Kentucky, Lexington, KY. Correspondence to: Enrique Diaz-Guzman, MD, University of Kentucky, 740 S Limestone St, L543 Kentucky Clinic, Lexington, KY 40536-0284; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378Ⲑchest.09-2847 746
showed muffled heart sounds without murmurs or gallops. Laboratory and Radiographic Findings Blood testing showed a hemoglobin concentration of 11.7 gⲐdL. Renal function, electrolyte and calcium levels, liver panel, and coagulation times were unremarkable. An ECG showed a normal sinus rhythm at a rate of 83 beatsⲐmin and normal axis. A plain chest radiograph showed cardiomegaly without pulmonary congestion or pleural effusions. An echocardiogram revealed the presence of a large circumferential pericardial effusion. The patient underwent a pericardiocentesis with a pigtail catheter insertion, which drained 1.6 L of bloody fluid. Cytologic examination of the pericardial fluid showed the presence of epithelioid cells, but was negative for malignancy. A gram stain showed numerous RBCs but no organisms. The results of cultures and special stains were negative. A CT scan of the chest after pericardiocentesis revealed the presence of a mediastinal mass (Figs 1, 2).
Figure 1. Axial CT scan section with IV contrast showing a soft tissue mass (asterisk) in the precarinal region extending inferiorly into the pericardial recess between the right pulmonary artery (arrow) and the ascending aorta (arrow head). Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
Figure 2. Axial CT scan section showing the mass (asterisk) in relation to the SVC (arrow). SVC 5 superior vena cava.
The patient was taken to the bronchoscopy suite for an airway examination and transbronchial needle aspiration of the mediastinal mass. Approximately five samples from the mass were obtained using a No. 21 cytology needle. Fine-needle aspirates were used to review for the presence of atypical epithelioid cells in a background of reactive bronchial epithelium, but no evidence of atypical lymphocytes or malignant cells was observed (specimen not shown). A mediastinoscopy was subsequently performed, obtaining multiple biopsy specimens from the mass (Fig 3).
www.chestpubs.org
Figure 3. High-power light micrograph of mediastinal biopsy tissue immunostained for the endothelial cell marker CD31, showing individual vacuolated malignant tumor cells with strong membrane positivity (original magnification 320).
What is the diagnosis?
CHEST / 138 / 3 / SEPTEMBER, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
747
Diagnosis: Epithelioid hemangioendothelioma of the anterior mediastinum
Discussion Epithelioid hemangioendothelioma (EHE) is a rare mesenchymal tumor of vascular origin, characterized by the presence of endothelial cells with primitive vascular differentiation, frequently described as having an epithelioid or histiocytoid appearance. Initially reported as an intravascular bronchioloalveolar tumor with a propensity for vascular invasion, EHE demonstrates histologic and clinical features intermediate between those of benign hemangioma and angiosarcoma. Because of the presence of epithelioid and histiocytoid cells, this malignancy has been confused with metastatic carcinoma, granulomatous diseases, or Langerhans cell histiocytosis. EHE has been described affecting many sites of the body, including lung, liver, bone, brain, lymph nodes, and breast. When involving the chest, the tumor more commonly affects the lung parenchyma, although several cases of mediastinal involvement have also been described. Pulmonary EHE is rare, with a recent report suggesting , 100 cases described in the literature. This neoplasm frequently presents as an incidental finding because patients are often asymptomatic at the time of diagnosis. Pulmonary EHE appears to be more common in women, with patients ranging in age from 7 to 76 years, with a mean onset of 35 years. CT scans of the chest show multiple perivascular nodules that range in size up to 2 cm, but most are , 1 cm. Other possible findings include hilar lymph node enlargement (9%) and pleural effusions (10%). Mediastinal involvement with this tumor is possible. A review of the medical literature in 1994 reported only 34 cases of mediastinal EHE published. Approximately 17 more cases describing EHE arising from the mediastinum have been reported since then. All cases except one describe involvement of the anterior mediastinum. The clinical presentation of mediastinal EHE is indistinguishable from other mediastinal masses, and most cases are discovered incidentally because patients remain asymptomatic until the tumor expands to involve adjacent structures. Symptoms related to mediastinal involvement are nonspecific and include chest pain, cough, dyspnea, dysphagia, stridor, wheezing, vocal cord paralysis, and complaints suggestive of superior vena cava (SVC) obstruction. The diagnosis of this neoplasm can be challenging because the tumor can arise from many organ systems and it may be difficult to determine if it represents a metastasis or a primary lesion. Although cytologic 748
and morphologic features may be suggestive of an alternate diagnosis, confirmation of an EHE requires a tissue biopsy, and most of the pulmonary or mediastinal cases of thoracic EHE have been diagnosed after a thoracoscopic biopsy or resection of the mass. The diagnosis is based on a combination of pathologic findings and the presence of immunohistochemical features showing tumor expression positivity for endothelial cells (ie, CD31, CD34, thrombomodulin, and FLI-1). In addition, EHE can focally stain with S-100 and smooth muscle actin. Electron microscopic examination of an EHE shows a cohesive population of cells characterized by large nuclei, irregular clumping of chromatin, and nucleoli. The cells contain abundant cytoplasm and intracytoplasmic intermediate (vimentin) filaments. Certain atypical histologic features such as cellular pleomorphism and increased mitotic activity indicate the potential for malignant behavior. The prognosis of EHE is variable. Distant metastases are present in up to 50% of patients, with hepatic metastases being the most common, followed by pleural metastases and lymph node metastases. Factors associated with a poor prognosis include the presence of atypical histologic findings, large size of the tumor, presence of pleural effusion, and clinical symptoms suggestive of extensive vascular, pulmonary, or pleural involvement. Spontaneous regression in asymptomatic patients has been described, with many patients living up to 15 to 20 years after surgical excision of the tumor. A review of EHE involving soft tissues noted an overall local recurrence rate of 13% within 48 months and a mortality rate of 13%. Atypical histologic findings suggestive of malignant potential are associated with a metastasis rate of 53% and a death rate of 31%, while the absence of these features is associated with a much better prognosis. There is no standard treatment of EHE. Surgical excision, chemotherapy with carboplatin or cisplatin plus etoposide, and treatment with interferon-a2b have been reported successful to achieve partial or complete remission. Clinical Course In our patient, review of the CT scan of the chest (Fig 1) revealed a uniform soft tissue mass (asterisk) (35 Hounsfield units) in the precarinal region, extending from above the level of the aortic arch of the neck vessels inferiorly into the pericardial recess between the right pulmonary artery (arrow) and the ascending aorta (arrowhead). The mass (asterisk) measured approximately 4.8 3 5 cm at the level of the carina and extended into the pericardial recess between the aortic root and the SVC, located in close contact with the SVC (arrow), which was displaced Postgraduate Education Corner
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
but patent (Fig 2). Because of the patient’s young age and family history, and the presence of a pericardial effusion, the initial diagnostic consideration was lymphoma. Nevertheless, the absence of lymphoid tissue in a transbronchial needle aspiration of the mass and the presence of epithelioid cells noted in the cytology examination suggested the possibility of an EHE. The patient underwent a diagnostic mediastinoscopy with biopsies. Pathologic examination showed a round, plump, clear-to-eosinophilic, moderately atypical tumor cell occupying a focally chondroid matrix, sometimes forming nests. Necrosis was present centripetally away from perivascular growth. Immunostains showed tumor cell positivity for CD31 (Fig 3) and thrombomodulin, and diffuse nuclear positivity for FLI-1. These finding were consistent with EHE. The patient was referred to an oncologist specialist who recommended radiation therapy and treatment with cisplatin. The patient initially improved after therapy, but a follow-up CT scan of the chest after 2 months revealed a significant increase in the size of the mass. Clinical Pearls 1. Because of its epithelioid nature, EHE can be confused with metastatic carcinoma. 2. Thoracic EHE affects the lung more commonly than the mediastinum. 3. The presence of cytologic features of epithelioid cells in a young patient with an anterior mediastinal mass must alert the clinician about the possibility of EHE. 4. The prognosis of EHE is variable, and surgical resection appears to be the only curative treatment,
www.chestpubs.org
although spontaneous regression of the tumor has been reported. Acknowledgments FinancialⲐnonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companiesⲐorganizations whose products or services may be discussed in this article.
Suggested Readings Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970-981. Suster S, Moran CA, Koss MN. Epithelioid hemangioendothelioma of the anterior mediastinum. Clinicopathologic, immunohistochemical, and ultrastructural analysis of 12 cases. Am J Surg Pathol. 1994;18(9):871-881. Erasmus JJ, McAdams HP, Carraway MS. A 63-year-old woman with weight loss and multiple lung nodules. Chest. 1997;111(1):236-238. Fletcher CDM, Unni KK, Mertens F, et al. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002. Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125(2):789-793. 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. Campos J, Otero E, Dominguez MJ, Gonzalez-Quintela A. Epithelioid hemangioendothelioma in the posterior mediastinum. Eur J Intern Med. 2007;18(4):331-332. Antic T, Staerkel G. Mediastinal epithelioid hemangioendothelioma metastatic to lymph nodes and pleural fluid: report of a case. Diagn Cytopathol. 2009;38(2):113-116.
CHEST / 138 / 3 / SEPTEMBER, 2010
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
749