J Gastrointest Canc (2014) 45 (Suppl 1):S275–S277 DOI 10.1007/s12029-014-9660-5
CASE REPORT
Epithelioid Hemangioendothelioma Presenting as Malignant Biliary Stricture Hamid Habibi & Bruno Bockorny & Kavitha Bagavathy & Frank Senatore & Madhavi Gorusu
Published online: 31 October 2014 # Springer Science+Business Media New York 2014
Case Presentation A 69-year-old Caucasian man with a history of hypertension, diabetes mellitus, and metastatic pulmonary epithelioid hemangioendothelioma presented with jaundice and pruritus. His epithelioid hemangioendothelioma was diagnosed 3 years prior when multiple pulmonary nodules were found during workup for cervical lymphadenopathy and normocytic anemia (Fig. 1). He was followed with active surveillance and serial chest computed tomography (CT) scans, which had confirmed stability of the pulmonary nodules. Recently, he began experiencing progressive tenderness on his cervical and supraclavicular lymph nodes. He had been taking moderate doses of acetaminophen for pain relief when he developed itching and yellowing of his skin. On examination, he was afebrile, normotensive, jaundice with icteric sclera, and had enlarged submandibular lymph nodes. There were no palpable abdominal masses, hepatosplenomegaly, or stigmata of end-stage liver disease. His laboratory data revealed an ALP 990 U/L, AST 338 U/L, ALT 505 U/L, total bilirubin 5.9 U/L, and direct bilirubin 4.5 U/L. He was empirically started on N-acetylcysteine for presumed acetaminophen toxicity despite an initial acetaminophen level of less than 15 mg/L. His right upper quadrant ultrasound showed a dilated common bile duct of 1.0 cm, mild dilation of the intrahepatic biliary ducts, and no evidence of cholelithiasis or pericholecystic fluid. Given his persistent symptoms
and worsening liver function tests, an endoscopic retrograde cholangiopancreatography (ERCP) was performed and showed a localized biliary stricture. The patient was treated with sphincterotomy and stent placement. A biopsy with billiary brushing cytology was performed, and the pathology was consistent with malignant epithelioid hemangioendothelioma. He was initially treated with sirolimus 3 mg daily. Nonetheless, he developed disease progression after 4 months with diffuse skin hyperpigmentation and thickening on the left shoulder and neck (Fig. 2). Biopsy of the skin confirmed metastatic epithelioid hemangioendothelioma and his treatment was switched to carboplatin, paclitaxel, and bevacizumab with significant improvement of the skin lesions. Unfortunately, 4 months after the commencement of chemotherapy, he was admitted to the hospital with Clostridium difficile colitis and acute hypoxic respiratory failure secondary to healthcare-associated pneumonia, and expired a few days after admission.
H. Habibi (*) : B. Bockorny : K. Bagavathy : F. Senatore Department of Internal Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA e-mail: [email protected] M. Gorusu Department of Hematology & Oncology, Hartford Hospital, Hartford, CT, USA
Fig. 1 Pulmonary nodules (right and left lobe)
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J Gastrointest Canc (2014) 45 (Suppl 1):S275–S277 Table 1 Patients treated with chemotherapy for primary pulmonary EHE without pleural involvement Chemotherapy base
Response
References
Partial remission
Belmont et al. [7]a
Disease progression
Kim et al. [8]a
Carboplatin and paclitaxel
Stability during chemo Ye et al. [9]a Stability during chemo Ye et al. [9] Carboplatin and etoposide Disease progression
Lopes et al. [10]a
Disease progression
Ye et al. [9]
Partial remission
Roudier-Pujol et al. [11]
Partial remission
Erasmus et al. [12]
Cisplatin, Paclitaxel Fig. 2 Diffuse skin hyperpigmentation and thickening on the left shoulder and neck
α-interferon
Discussion Epithelioid hemangioendothelioma is a rare vascular neoplasm with intermediate malignant potential and a clinical course between benign hemangioma and angiosarcoma, resulting in difficulty predicting prognosis [1, 2]. It has a tendency to develop multifocal disease, primarily in the liver and lungs. Other affected organs include bones and soft tissues of the extremities [3]. Typically, EHE affects young patients with a mean age of diagnosis of 40 years and is twice as common in women [4]. Although its etiology remains unclear, immunohistochemical and electron microscopy studies have shown that EHE has an endothelial lineage, displaying immunoreactivity to some or all of the vascular-endothelial markers including CD31, CD34, and factor VIII [5]. In our patient, the immunohistochemistry
Fig. 3 Factor VIII and CD 31
Disease progression
Marsh et al. [13]
Partial remission
Radzikowska et al. [14]
Azathioprine No progression
Marsh et al. [15]
No progression
Ledson et al. [16]
Mitomycin, 5-FU, Disease progression cyclophosphamide, vincristine, tegafur, or cisplatin a
Kitaichi et al. [17]
Included Bevacizumab in regimen
was strongly positive for CD31, consistent with epithelioid hemangioendothelioma (Fig. 3). Many treatment approaches have been advocated for in the medical literature, yet given the rarity of this tumor, no standard treatment has been established to date. EHE tumors have
J Gastrointest Canc (2014) 45 (Suppl 1):S275–S277
been shown to be poorly responsive to radiation and chemotherapy [1]. While, surgical resection has been recommended in cases of a solitary or limited number of EHE lesions, watchful waiting may be an acceptable option in asymptomatic patients with no evidence of rapidly progressive disease [6]. Although there have been no large studies evaluating the benefits of chemotherapy in advanced and metastatic EHE, several case reports have demonstrated the benefits of chemotherapy in this setting. The most common chemotherapy employed is a platinum-based regimen, often with combination paclitaxel and bevacizumab (Table 1) [5, 18]. Additionally, some patients have attained stable disease or even partial response for extended periods with immune modulating agents such as thalidomide and interferon alfa-2b [19, 20]. The prognosis of EHE is remarkably unpredictable, with life expectancy ranging from 1 to 15 years [3]. A large systematic review of 80 cases of EHE reported a 5-year survival probability of 60 %. Interestingly, multivariate analysis showed a statistically worse survival in patients with hemorrhagic symptoms such as hemoptysis and hemorrhagic pleural effusion. In fact, the 5-year survival of patients with pleural hemorrhagic effusion was 2 %, whereas survival of population without effusion was 73 % (p=0.001). Moreover, metastatic progression of the cancer was the cause of death in 38 % of cases, with a predominance of liver and bone metastases. In our case, the patient was diagnosed with metastatic pulmonary EHE and followed with watchful waiting for 3 years, showing slow progression of asymptomatic pulmonary nodules. Unfortunately, he subsequently developed obstructive jaundice and imaging studies showed extensive metastatic disease to the liver and abdominal lymph nodes. An ERCP revealed a malignant biliary stricture treated with sphincterotomy and stent placement. The patient was started on sirolimus with poor response. Four months later, his disease progressed with metastasis to skin and cervical lymph nodes. At this point, palliative chemotherapy with carboplatin, paclitaxel, and bevacizumab was initiated but the patient expired after the third cycle due to progression of the disease. In summary, we described a case of a patient who presented with aggressive metastatic disease to the biliary tree, skin, and lymph nodes after more than 3 years of watchful waiting with follow up. He had very poor response to chemoimmunotherapy and expired shortly thereafter. To our knowledge, this is the first case of EHE diagnosed with ERCP and biliary brushing cytology.
Conflict of Interest The authors do not have any conflict of interest or financial disclosures.
S277
References 1. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer. 2006;107:2108–21. 2. Uchimura K, Nakamuta M, Osoegawa M, et al. Hepatic epithelioid hemangioendothelioma. J Clin Gastroenterol. 2001;32:431–4. 3. Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125:789–92. Liver Transpl. 2010 Feb;16(2):191–7. 10.1002/lt.21964. 4. Bagan P, Hassan M, Le Pimpec Barthes F, Peyrard S, Souilamas R, Danel C, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: a review of the literature. Ann Thorac Surg. 2006;82(6):2010–3. 5. 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):1491–6. 6. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: Insights from an internet registry in the study of a rare cancer. Chest. 2011;140:1312–8. 7. Belmont L, Zemoura L, Couderc LJ. Pulmonary epithelioid haemangioendothelioma and bevacizumab. J Thorac Oncol. 2008;3:557–8. 8. Kim YH, Mishima M, Miyagawa-Hayashino A. Treatment of pulmonary epithelioid hemangioendothelioma with bevacizumab. J Thorac Oncol. 2010;5:1107–8. 9. Ye B, Li W, Feng J, et al. Treatment of pulmonary epithelioid hmangioendothelioma with combination chemotherapy: Report of three cases and review of the literature. Oncol Lett. 2013;5:1491–6. 10. Lopes T, Clemente S, Feliciano A, et al. Pulmonary epithelioid hemangioendothelioma–rarity, diagnosis and treatment difficulties. Rev Port Pneumol. 2009;15:1167–74. 11. 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. 12. Erasmus JJ, McAdams HP, Carraway MS. A 63-year-old woman with weight loss and multiple lung nodules. Chest. 1997;111:236–8. 13. Marsh RW, Walker MH, Jacob G, et al. Breast implants as a possible etiology of epithelioid hemangioendothelioma and successful therapy with interferon-alpha2. Breast J. 2005;11:257–61. 14. Radzikowska E, Szczepulska-Wojcik E, Chabowski M, et al. Pulmonary epithelioid haemangioendothelioma–interferon 2-alpha treatment—Case report. Pneumonol Alergol Pol. 2008;76:281–5. 15. Marsh K, Kenyon WE, Earis JE, et al. Intravascular bronchioloalveolar tumour. Thorax. 1982;37:474–5. 16. Ledson MJ, Convery R, Carty A, Evans CC. Epithelioid haemangioendothelioma. Thorax. 1999;54:560–1. 17. 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. 18. Emamaullee JA, Edgar R, Toso C, et al. Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: Implications for treatment and surgical management. Liver Transpl. 2010;16(2):191–7. 19. Raphael C, Hudson E, Williams L, et al. Successful treatment of metastatic hepatic epithelioid hemangioendothelioma with thalidomide: a case report. J Med Case Rep. 2010;4:413. 20. Kassam A, Mandel K. Metastatic hepatic epithelioid hemangioendothelioma in a teenage girl. J Pediatr Hematol Oncol. 2008;30:550–2.
CASE REPORT
Epithelioid Hemangioendothelioma Presenting as Malignant Biliary Stricture Hamid Habibi & Bruno Bockorny & Kavitha Bagavathy & Frank Senatore & Madhavi Gorusu
Published online: 31 October 2014 # Springer Science+Business Media New York 2014
Case Presentation A 69-year-old Caucasian man with a history of hypertension, diabetes mellitus, and metastatic pulmonary epithelioid hemangioendothelioma presented with jaundice and pruritus. His epithelioid hemangioendothelioma was diagnosed 3 years prior when multiple pulmonary nodules were found during workup for cervical lymphadenopathy and normocytic anemia (Fig. 1). He was followed with active surveillance and serial chest computed tomography (CT) scans, which had confirmed stability of the pulmonary nodules. Recently, he began experiencing progressive tenderness on his cervical and supraclavicular lymph nodes. He had been taking moderate doses of acetaminophen for pain relief when he developed itching and yellowing of his skin. On examination, he was afebrile, normotensive, jaundice with icteric sclera, and had enlarged submandibular lymph nodes. There were no palpable abdominal masses, hepatosplenomegaly, or stigmata of end-stage liver disease. His laboratory data revealed an ALP 990 U/L, AST 338 U/L, ALT 505 U/L, total bilirubin 5.9 U/L, and direct bilirubin 4.5 U/L. He was empirically started on N-acetylcysteine for presumed acetaminophen toxicity despite an initial acetaminophen level of less than 15 mg/L. His right upper quadrant ultrasound showed a dilated common bile duct of 1.0 cm, mild dilation of the intrahepatic biliary ducts, and no evidence of cholelithiasis or pericholecystic fluid. Given his persistent symptoms
and worsening liver function tests, an endoscopic retrograde cholangiopancreatography (ERCP) was performed and showed a localized biliary stricture. The patient was treated with sphincterotomy and stent placement. A biopsy with billiary brushing cytology was performed, and the pathology was consistent with malignant epithelioid hemangioendothelioma. He was initially treated with sirolimus 3 mg daily. Nonetheless, he developed disease progression after 4 months with diffuse skin hyperpigmentation and thickening on the left shoulder and neck (Fig. 2). Biopsy of the skin confirmed metastatic epithelioid hemangioendothelioma and his treatment was switched to carboplatin, paclitaxel, and bevacizumab with significant improvement of the skin lesions. Unfortunately, 4 months after the commencement of chemotherapy, he was admitted to the hospital with Clostridium difficile colitis and acute hypoxic respiratory failure secondary to healthcare-associated pneumonia, and expired a few days after admission.
H. Habibi (*) : B. Bockorny : K. Bagavathy : F. Senatore Department of Internal Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA e-mail: [email protected] M. Gorusu Department of Hematology & Oncology, Hartford Hospital, Hartford, CT, USA
Fig. 1 Pulmonary nodules (right and left lobe)
S276
J Gastrointest Canc (2014) 45 (Suppl 1):S275–S277 Table 1 Patients treated with chemotherapy for primary pulmonary EHE without pleural involvement Chemotherapy base
Response
References
Partial remission
Belmont et al. [7]a
Disease progression
Kim et al. [8]a
Carboplatin and paclitaxel
Stability during chemo Ye et al. [9]a Stability during chemo Ye et al. [9] Carboplatin and etoposide Disease progression
Lopes et al. [10]a
Disease progression
Ye et al. [9]
Partial remission
Roudier-Pujol et al. [11]
Partial remission
Erasmus et al. [12]
Cisplatin, Paclitaxel Fig. 2 Diffuse skin hyperpigmentation and thickening on the left shoulder and neck
α-interferon
Discussion Epithelioid hemangioendothelioma is a rare vascular neoplasm with intermediate malignant potential and a clinical course between benign hemangioma and angiosarcoma, resulting in difficulty predicting prognosis [1, 2]. It has a tendency to develop multifocal disease, primarily in the liver and lungs. Other affected organs include bones and soft tissues of the extremities [3]. Typically, EHE affects young patients with a mean age of diagnosis of 40 years and is twice as common in women [4]. Although its etiology remains unclear, immunohistochemical and electron microscopy studies have shown that EHE has an endothelial lineage, displaying immunoreactivity to some or all of the vascular-endothelial markers including CD31, CD34, and factor VIII [5]. In our patient, the immunohistochemistry
Fig. 3 Factor VIII and CD 31
Disease progression
Marsh et al. [13]
Partial remission
Radzikowska et al. [14]
Azathioprine No progression
Marsh et al. [15]
No progression
Ledson et al. [16]
Mitomycin, 5-FU, Disease progression cyclophosphamide, vincristine, tegafur, or cisplatin a
Kitaichi et al. [17]
Included Bevacizumab in regimen
was strongly positive for CD31, consistent with epithelioid hemangioendothelioma (Fig. 3). Many treatment approaches have been advocated for in the medical literature, yet given the rarity of this tumor, no standard treatment has been established to date. EHE tumors have
J Gastrointest Canc (2014) 45 (Suppl 1):S275–S277
been shown to be poorly responsive to radiation and chemotherapy [1]. While, surgical resection has been recommended in cases of a solitary or limited number of EHE lesions, watchful waiting may be an acceptable option in asymptomatic patients with no evidence of rapidly progressive disease [6]. Although there have been no large studies evaluating the benefits of chemotherapy in advanced and metastatic EHE, several case reports have demonstrated the benefits of chemotherapy in this setting. The most common chemotherapy employed is a platinum-based regimen, often with combination paclitaxel and bevacizumab (Table 1) [5, 18]. Additionally, some patients have attained stable disease or even partial response for extended periods with immune modulating agents such as thalidomide and interferon alfa-2b [19, 20]. The prognosis of EHE is remarkably unpredictable, with life expectancy ranging from 1 to 15 years [3]. A large systematic review of 80 cases of EHE reported a 5-year survival probability of 60 %. Interestingly, multivariate analysis showed a statistically worse survival in patients with hemorrhagic symptoms such as hemoptysis and hemorrhagic pleural effusion. In fact, the 5-year survival of patients with pleural hemorrhagic effusion was 2 %, whereas survival of population without effusion was 73 % (p=0.001). Moreover, metastatic progression of the cancer was the cause of death in 38 % of cases, with a predominance of liver and bone metastases. In our case, the patient was diagnosed with metastatic pulmonary EHE and followed with watchful waiting for 3 years, showing slow progression of asymptomatic pulmonary nodules. Unfortunately, he subsequently developed obstructive jaundice and imaging studies showed extensive metastatic disease to the liver and abdominal lymph nodes. An ERCP revealed a malignant biliary stricture treated with sphincterotomy and stent placement. The patient was started on sirolimus with poor response. Four months later, his disease progressed with metastasis to skin and cervical lymph nodes. At this point, palliative chemotherapy with carboplatin, paclitaxel, and bevacizumab was initiated but the patient expired after the third cycle due to progression of the disease. In summary, we described a case of a patient who presented with aggressive metastatic disease to the biliary tree, skin, and lymph nodes after more than 3 years of watchful waiting with follow up. He had very poor response to chemoimmunotherapy and expired shortly thereafter. To our knowledge, this is the first case of EHE diagnosed with ERCP and biliary brushing cytology.
Conflict of Interest The authors do not have any conflict of interest or financial disclosures.
S277
References 1. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer. 2006;107:2108–21. 2. Uchimura K, Nakamuta M, Osoegawa M, et al. Hepatic epithelioid hemangioendothelioma. J Clin Gastroenterol. 2001;32:431–4. 3. Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: an unusual case and a review of the literature. Chest. 2004;125:789–92. Liver Transpl. 2010 Feb;16(2):191–7. 10.1002/lt.21964. 4. Bagan P, Hassan M, Le Pimpec Barthes F, Peyrard S, Souilamas R, Danel C, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: a review of the literature. Ann Thorac Surg. 2006;82(6):2010–3. 5. 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):1491–6. 6. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: Insights from an internet registry in the study of a rare cancer. Chest. 2011;140:1312–8. 7. Belmont L, Zemoura L, Couderc LJ. Pulmonary epithelioid haemangioendothelioma and bevacizumab. J Thorac Oncol. 2008;3:557–8. 8. Kim YH, Mishima M, Miyagawa-Hayashino A. Treatment of pulmonary epithelioid hemangioendothelioma with bevacizumab. J Thorac Oncol. 2010;5:1107–8. 9. Ye B, Li W, Feng J, et al. Treatment of pulmonary epithelioid hmangioendothelioma with combination chemotherapy: Report of three cases and review of the literature. Oncol Lett. 2013;5:1491–6. 10. Lopes T, Clemente S, Feliciano A, et al. Pulmonary epithelioid hemangioendothelioma–rarity, diagnosis and treatment difficulties. Rev Port Pneumol. 2009;15:1167–74. 11. 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. 12. Erasmus JJ, McAdams HP, Carraway MS. A 63-year-old woman with weight loss and multiple lung nodules. Chest. 1997;111:236–8. 13. Marsh RW, Walker MH, Jacob G, et al. Breast implants as a possible etiology of epithelioid hemangioendothelioma and successful therapy with interferon-alpha2. Breast J. 2005;11:257–61. 14. Radzikowska E, Szczepulska-Wojcik E, Chabowski M, et al. Pulmonary epithelioid haemangioendothelioma–interferon 2-alpha treatment—Case report. Pneumonol Alergol Pol. 2008;76:281–5. 15. Marsh K, Kenyon WE, Earis JE, et al. Intravascular bronchioloalveolar tumour. Thorax. 1982;37:474–5. 16. Ledson MJ, Convery R, Carty A, Evans CC. Epithelioid haemangioendothelioma. Thorax. 1999;54:560–1. 17. 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. 18. Emamaullee JA, Edgar R, Toso C, et al. Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: Implications for treatment and surgical management. Liver Transpl. 2010;16(2):191–7. 19. Raphael C, Hudson E, Williams L, et al. Successful treatment of metastatic hepatic epithelioid hemangioendothelioma with thalidomide: a case report. J Med Case Rep. 2010;4:413. 20. Kassam A, Mandel K. Metastatic hepatic epithelioid hemangioendothelioma in a teenage girl. J Pediatr Hematol Oncol. 2008;30:550–2.
