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Spontaneous complete regression of hepatic epithelioid haemangioendothelioma
Case Report
Spontaneous complete regression of hepatic epithelioid haemangioendothelioma Zaher K Otrock, Aghiad Al-Kutoubi, Mireille M Kattar, Ghazi Zaatari, Assaad Soweid
A 75-year-old woman presented with a 3-month history of upper abdominal pain associated with distention and change in bowel habits. She also reported fatigue and weight loss of 5 kg in the preceding 4 months. She had no history of hepatitis, blood transfusions, or alcohol intake. Her family history was negative for malignant disease, and she was not taking any prescribed drugs. On examination, the patient was pale, but not icteric; vital signs were within normal limits. She had mild tenderness in the right upper quadrant of the abdomen without hepatosplenomegaly. Laboratory results were as follows (reference values in parentheses): alanine aminotransferase 13 U/L (<50 U/L); aspartate aminotransferase 9 U/L (<50 U/L); γ glutamyl transferase 10 U/L (<50 U/L); alkaline phosphatase 105 U/L (<120 U/L); α fetoprotein 1·7 μg/L (1·0–9·0 U/mL); cancer antigen (CA) 19-9 6·6 U/mL (0–37 U/mL); carcinoembryonic antigen 1·8 µg/L (0–5 µg/L); and CA 125 16·5 U/mL (0–40 U/mL). Further investigation included helical CT of the chest, abdomen, and pelvis, which showed multiple suspicious lesions in the liver (figure 1A) and a few lesions in the lung bases. Fine-needle aspiration and core biopsy of the liver lesions were done, and the biopsy sample showed epithelioid tumour cells arranged in small nests and short cords in desmoplastic stroma. The tumour cells had abundant eosinophilic cytoplasm and moderate nuclear pleiomorphism; multinucleated cells and occasional mitoses were noted (figure 2A). Some cells had intracellular lumina that were thought at first to be vacuoles or glandular lumina. On the basis of these findings, the tumour was initially diagnosed as a poorly differentiated carcinoma. Work-up—including
upper and lower gastrointestinal endoscopy, ultrasonography, and mammography—were within normal limits. The patient refused any type of treatment, and was discharged home. Nevertheless, the patient was followed up regularly by her primary physician. 20 months later, after an improvement in her clinical condition and a weight gain of more than 10 kg, a repeat CT showed resolution of all hepatic lesions (figure 1B). The patient was followed up for more than 3·5 years and continues to do well. In view of the clinical behaviour of this neoplasm, pathological material was reassessed and immunostaining was done. Tumour cells were positive for vascular markers CD34 (figure 2B) and CD31, and were negative for epithelial markers (including cytokeratin 7, cytokeratin 20, cytokeratins 8/18 (Cam 5·2), and cytokeratins AE1/AE3); α fetoprotein; oestrogen receptors and progesterone receptors; and thyroid transcription factor 1 (TTF1, which is usually expressed in lung carcinoma). The morphological and immunophenotypic features are diagnostic of epithelioid haemangioendothelioma. Epithelioid haemangioendothelioma is an indolent mesenchymal neoplasm that arises from endothelial cells. This rare vascular neoplasm occurs frequently in soft tissues, liver, lung, bone, and spleen. It is a solid tumour of low-grade malignancy, consisting of epithelioid-like endothelial cells,1 and can be misdiagnosed as carcinoma—primary or metastatic.1 The clinical features of epithelioid haemangioendothelioma of the liver have been reviewed by several researchers.2,3 Makhlouf and colleagues2 analysed 137 patients with epithelioid haemangioendothelioma
Lancet Oncol 2006; 7: 439–41 Department of Internal Medicine (Z K Otrock MD, A Soweid A MD), Department of Diagnostic Radiology (A Al-Kutoubi MD), and Department of Pathology and Laboratory Medicine (M M Kattar MD, G Zaatari MD), American University of Beirut Medical Centre, Beirut, Lebanon Correspondence to: Dr Assaad M Soweid, Division of Gastroenterology, American University of Beirut Medical Centre, PO Box 113-6044, Hamra 11 03–2090, Beirut, Lebanon [email protected]
Figure 1: CT section through liver at diagnosis (A) and 20 months after diagnosis (B) Images obtained in late portal phase after intravenous contrast.
http://oncology.thelancet.com Vol 7 May 2006
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Case Report
Figure 2: Histological analyses of liver mass (A) Needle-core biopsy: tumour is made of short cords and small nests of epithelioid tumour cells in desmoplastic stroma; some cells show intracellular lumina (arrow; haematoxylin and eosin stain, magnification ×400). (B) Immunostaining for CD34 shows diffuse and intense staining of tumour cells and a concentric membranous pattern (magnification ×400).
of the liver. About 37 (27%) of patients had regional lymph-node involvement in addition to involvement of the lung, peritoneum, and retroperitoneum. Makhlouf and colleagues2 noted that: clinical diagnosis was difficult because of the presence of non-specific symptoms such as abdominal pain in the right upper quadrant and weight loss; the tumour occurred more frequently in women than in men (61% vs 39%); median age at presentation was 46 years (range 12–86); and that 5-year survival was 43%. Histologically, most patients have a low degree of pleiomorphism and mitotic activity.1 The tumour is frequently misdiagnosed, and differential diagnosis might be difficult because of pleiomorphism and various tumour patterns.4 However, positive immunostaining for vascular markers, including factor VIII, CD31, and CD34, and no staining for epithelial markers enables a definitive diagnosis. The clinical course of epithelioid haemangioendothelioma varies from favourable (with protracted survival, perhaps without treatment), to that of rapidly progressive disease with fatal outcome.5 In addition to primary liver epithelioid haemangioendothelioma with lung metastases,6 hepatic metastases secondary to a primary pulmonary epithelioid haemangioendothelioma have been reported.7 For our patient, definition of whether the tumour originated in the liver and spread to the lungs, or vice versa, was difficult. The patient was admitted to hospital for assessment of cardiac symptoms more than 3 years after initial presentation. Chest radiography showed resolution of the previously identified basilar lung nodules and only poorly defined shadowing in the left lower lung (figure 3). Hepatic epithelioid haemangioendothelioma is treated with radical hepatic resection and liver transplantation.4 However, if metastases are identifiable, no surgery should be attempted. The effectiveness of chemotherapy and radiotherapy remains controversial. 440
Without any type of treatment, our patient improved and gained weight, and follow-up CT showed complete regression of the liver lesions with faint bibasal pulmonary lesions remaining. About 3·5 years after diagnosis, the patient is doing well. The natural course of epithelioid haemangioendothelioma varies substantially depending on organs involved. Prognosis seems to be worse if both liver and lung are involved. Slow progression and partial spontaneous regression might occur, especially in asymptomatic patients.7 Kitaichi and co-workers7 reported partial spontaneous regression of pulmonary epithelioid haemangioendothelioma in three of 21 patients. The spontaneous complete regression of a malignant tumour is very rare.8 Spontaneous regression of cancers has been defined as the disappearance of malignant disease without any type of medical treatment or with inadequate treatment.9 Everson and Cole9 reported only 176 cases of spontaneous regression of cancers from
Figure 3: Chest radiographs (A) At first presentation, showing bibasilar poorly defined densities with nodules (arrow). (B) 3 years after first presentation, showing resolution of basilar lung nodules and only poorly defined shadowing in left lower lung.
http://oncology.thelancet.com Vol 7 May 2006
Case Report
1900 to 1964, with an estimated incidence of one in 100 000 patients with cancer. When the first observations of partial spontaneous regressions were made, interest was raised regarding possible biological mechanisms; however, these events remain unexplained. Systemic effects such as immune responses have been postulated as possible mechanisms because regression has been noted not only at primary tumour sites, but also in metastatic foci.10 We have reviewed medical reports published in English, using MEDLINE from 1966 until November, 2005, for the records of spontaneous regression. To our knowledge, no occurrence of spontaneous complete regression of epithelioid haemangioendothelioma in the liver has been reported apart from that noted here. Our patient had documented complete regression of hepatic lesions without receiving any medical, surgical, or alternative treatment; there were no evident changes in her lifestyle or diet. In summary, to our knowledge, we have reported the first case of complete spontaneous regression of epithelioid haemangioendothelioma of the liver. The precise cause of regression is unknown. We think that accumulation and careful analysis of clinical data for patients with spontaneously regressing tumours will contribute to our understanding of this enigmatic event and to future advances in the treatment of such tumours.
http://oncology.thelancet.com Vol 7 May 2006
Conflicts of interest We declare no conflicts of interest. References 1 Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982; 50: 970–81. 2 Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 562–82. 3 Lauffer JM, Zimmermann A, Krahenbuhl L, et al. Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor. Cancer 1996; 78: 2318–27. 4 d’Annibale M, Piovanello P, Carlini P, et al. Epithelioid hemangioendothelioma of the liver: case report and review of the literature. Transplant Proc 2002; 34: 1248–51. 5 Ekfors TO, Joensuu K, Toivio I, et al. Fatal epithelioid haemangioendothelioma presenting in the lung and liver. Virchows Arch A Pathol Anat Histopathol 1986; 410: 9–16. 6 Fukayama M, Nihei Z, Takizawa T, et al. Malignant epithelioid hemangioendothelioma of the liver, spreading through the hepatic veins. Virchows Arch A Pathol Anat Histopathol 1984; 404: 275–87. 7 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. 8 Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncol 1981; 17: 201–09. 9 Everson TC, Cole WH. Spontaneous regression of cancer. Philadelphia: Saunders, 1966: 6–7. 10 Kato H, Nakamura M, Muramatsu M, et al. Spontaneous regression of hepatocellular carcinoma: two case reports and a literature review. Hepatol Res 2004; 29: 180–90.
441
Spontaneous complete regression of hepatic epithelioid haemangioendothelioma Zaher K Otrock, Aghiad Al-Kutoubi, Mireille M Kattar, Ghazi Zaatari, Assaad Soweid
A 75-year-old woman presented with a 3-month history of upper abdominal pain associated with distention and change in bowel habits. She also reported fatigue and weight loss of 5 kg in the preceding 4 months. She had no history of hepatitis, blood transfusions, or alcohol intake. Her family history was negative for malignant disease, and she was not taking any prescribed drugs. On examination, the patient was pale, but not icteric; vital signs were within normal limits. She had mild tenderness in the right upper quadrant of the abdomen without hepatosplenomegaly. Laboratory results were as follows (reference values in parentheses): alanine aminotransferase 13 U/L (<50 U/L); aspartate aminotransferase 9 U/L (<50 U/L); γ glutamyl transferase 10 U/L (<50 U/L); alkaline phosphatase 105 U/L (<120 U/L); α fetoprotein 1·7 μg/L (1·0–9·0 U/mL); cancer antigen (CA) 19-9 6·6 U/mL (0–37 U/mL); carcinoembryonic antigen 1·8 µg/L (0–5 µg/L); and CA 125 16·5 U/mL (0–40 U/mL). Further investigation included helical CT of the chest, abdomen, and pelvis, which showed multiple suspicious lesions in the liver (figure 1A) and a few lesions in the lung bases. Fine-needle aspiration and core biopsy of the liver lesions were done, and the biopsy sample showed epithelioid tumour cells arranged in small nests and short cords in desmoplastic stroma. The tumour cells had abundant eosinophilic cytoplasm and moderate nuclear pleiomorphism; multinucleated cells and occasional mitoses were noted (figure 2A). Some cells had intracellular lumina that were thought at first to be vacuoles or glandular lumina. On the basis of these findings, the tumour was initially diagnosed as a poorly differentiated carcinoma. Work-up—including
upper and lower gastrointestinal endoscopy, ultrasonography, and mammography—were within normal limits. The patient refused any type of treatment, and was discharged home. Nevertheless, the patient was followed up regularly by her primary physician. 20 months later, after an improvement in her clinical condition and a weight gain of more than 10 kg, a repeat CT showed resolution of all hepatic lesions (figure 1B). The patient was followed up for more than 3·5 years and continues to do well. In view of the clinical behaviour of this neoplasm, pathological material was reassessed and immunostaining was done. Tumour cells were positive for vascular markers CD34 (figure 2B) and CD31, and were negative for epithelial markers (including cytokeratin 7, cytokeratin 20, cytokeratins 8/18 (Cam 5·2), and cytokeratins AE1/AE3); α fetoprotein; oestrogen receptors and progesterone receptors; and thyroid transcription factor 1 (TTF1, which is usually expressed in lung carcinoma). The morphological and immunophenotypic features are diagnostic of epithelioid haemangioendothelioma. Epithelioid haemangioendothelioma is an indolent mesenchymal neoplasm that arises from endothelial cells. This rare vascular neoplasm occurs frequently in soft tissues, liver, lung, bone, and spleen. It is a solid tumour of low-grade malignancy, consisting of epithelioid-like endothelial cells,1 and can be misdiagnosed as carcinoma—primary or metastatic.1 The clinical features of epithelioid haemangioendothelioma of the liver have been reviewed by several researchers.2,3 Makhlouf and colleagues2 analysed 137 patients with epithelioid haemangioendothelioma
Lancet Oncol 2006; 7: 439–41 Department of Internal Medicine (Z K Otrock MD, A Soweid A MD), Department of Diagnostic Radiology (A Al-Kutoubi MD), and Department of Pathology and Laboratory Medicine (M M Kattar MD, G Zaatari MD), American University of Beirut Medical Centre, Beirut, Lebanon Correspondence to: Dr Assaad M Soweid, Division of Gastroenterology, American University of Beirut Medical Centre, PO Box 113-6044, Hamra 11 03–2090, Beirut, Lebanon [email protected]
Figure 1: CT section through liver at diagnosis (A) and 20 months after diagnosis (B) Images obtained in late portal phase after intravenous contrast.
http://oncology.thelancet.com Vol 7 May 2006
439
Case Report
Figure 2: Histological analyses of liver mass (A) Needle-core biopsy: tumour is made of short cords and small nests of epithelioid tumour cells in desmoplastic stroma; some cells show intracellular lumina (arrow; haematoxylin and eosin stain, magnification ×400). (B) Immunostaining for CD34 shows diffuse and intense staining of tumour cells and a concentric membranous pattern (magnification ×400).
of the liver. About 37 (27%) of patients had regional lymph-node involvement in addition to involvement of the lung, peritoneum, and retroperitoneum. Makhlouf and colleagues2 noted that: clinical diagnosis was difficult because of the presence of non-specific symptoms such as abdominal pain in the right upper quadrant and weight loss; the tumour occurred more frequently in women than in men (61% vs 39%); median age at presentation was 46 years (range 12–86); and that 5-year survival was 43%. Histologically, most patients have a low degree of pleiomorphism and mitotic activity.1 The tumour is frequently misdiagnosed, and differential diagnosis might be difficult because of pleiomorphism and various tumour patterns.4 However, positive immunostaining for vascular markers, including factor VIII, CD31, and CD34, and no staining for epithelial markers enables a definitive diagnosis. The clinical course of epithelioid haemangioendothelioma varies from favourable (with protracted survival, perhaps without treatment), to that of rapidly progressive disease with fatal outcome.5 In addition to primary liver epithelioid haemangioendothelioma with lung metastases,6 hepatic metastases secondary to a primary pulmonary epithelioid haemangioendothelioma have been reported.7 For our patient, definition of whether the tumour originated in the liver and spread to the lungs, or vice versa, was difficult. The patient was admitted to hospital for assessment of cardiac symptoms more than 3 years after initial presentation. Chest radiography showed resolution of the previously identified basilar lung nodules and only poorly defined shadowing in the left lower lung (figure 3). Hepatic epithelioid haemangioendothelioma is treated with radical hepatic resection and liver transplantation.4 However, if metastases are identifiable, no surgery should be attempted. The effectiveness of chemotherapy and radiotherapy remains controversial. 440
Without any type of treatment, our patient improved and gained weight, and follow-up CT showed complete regression of the liver lesions with faint bibasal pulmonary lesions remaining. About 3·5 years after diagnosis, the patient is doing well. The natural course of epithelioid haemangioendothelioma varies substantially depending on organs involved. Prognosis seems to be worse if both liver and lung are involved. Slow progression and partial spontaneous regression might occur, especially in asymptomatic patients.7 Kitaichi and co-workers7 reported partial spontaneous regression of pulmonary epithelioid haemangioendothelioma in three of 21 patients. The spontaneous complete regression of a malignant tumour is very rare.8 Spontaneous regression of cancers has been defined as the disappearance of malignant disease without any type of medical treatment or with inadequate treatment.9 Everson and Cole9 reported only 176 cases of spontaneous regression of cancers from
Figure 3: Chest radiographs (A) At first presentation, showing bibasilar poorly defined densities with nodules (arrow). (B) 3 years after first presentation, showing resolution of basilar lung nodules and only poorly defined shadowing in left lower lung.
http://oncology.thelancet.com Vol 7 May 2006
Case Report
1900 to 1964, with an estimated incidence of one in 100 000 patients with cancer. When the first observations of partial spontaneous regressions were made, interest was raised regarding possible biological mechanisms; however, these events remain unexplained. Systemic effects such as immune responses have been postulated as possible mechanisms because regression has been noted not only at primary tumour sites, but also in metastatic foci.10 We have reviewed medical reports published in English, using MEDLINE from 1966 until November, 2005, for the records of spontaneous regression. To our knowledge, no occurrence of spontaneous complete regression of epithelioid haemangioendothelioma in the liver has been reported apart from that noted here. Our patient had documented complete regression of hepatic lesions without receiving any medical, surgical, or alternative treatment; there were no evident changes in her lifestyle or diet. In summary, to our knowledge, we have reported the first case of complete spontaneous regression of epithelioid haemangioendothelioma of the liver. The precise cause of regression is unknown. We think that accumulation and careful analysis of clinical data for patients with spontaneously regressing tumours will contribute to our understanding of this enigmatic event and to future advances in the treatment of such tumours.
http://oncology.thelancet.com Vol 7 May 2006
Conflicts of interest We declare no conflicts of interest. References 1 Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982; 50: 970–81. 2 Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 562–82. 3 Lauffer JM, Zimmermann A, Krahenbuhl L, et al. Epithelioid hemangioendothelioma of the liver. A rare hepatic tumor. Cancer 1996; 78: 2318–27. 4 d’Annibale M, Piovanello P, Carlini P, et al. Epithelioid hemangioendothelioma of the liver: case report and review of the literature. Transplant Proc 2002; 34: 1248–51. 5 Ekfors TO, Joensuu K, Toivio I, et al. Fatal epithelioid haemangioendothelioma presenting in the lung and liver. Virchows Arch A Pathol Anat Histopathol 1986; 410: 9–16. 6 Fukayama M, Nihei Z, Takizawa T, et al. Malignant epithelioid hemangioendothelioma of the liver, spreading through the hepatic veins. Virchows Arch A Pathol Anat Histopathol 1984; 404: 275–87. 7 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. 8 Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncol 1981; 17: 201–09. 9 Everson TC, Cole WH. Spontaneous regression of cancer. Philadelphia: Saunders, 1966: 6–7. 10 Kato H, Nakamura M, Muramatsu M, et al. Spontaneous regression of hepatocellular carcinoma: two case reports and a literature review. Hepatol Res 2004; 29: 180–90.
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