Hepatic epithelioid hemangioendothelioma (HEHE) is a malignant vascular tumor known for its rarity. The different types of this hepatic tumor (single, multiple-nodular or diffused) indicate different prognosis and treatment plans. However, the heterogenic clinical manifestation creates a dilemma and a wide range of challenges when attending to HEHE patients. This review addresses the unique profile and clinical challenges that complicate the diagnosis and treatment of HEHE while focusing on current therapeutic strategies and their limitations.

The unclear etiology is a challenging feature of HEHE. The exact involvement of potential risk factors and mechanism of development are still undefined. Relevant genetic alterations like WWTR1-CAMTA1 fusion have been investigated; however, they are only applicable as diagnostic markers and their influence on therapeutic efficacy is largely unknown. Other characteristics include asymptomatic manifestation, lack of unique hepatic functional alterations, high rates of misdiagnosis and late-stage identification when metastases already exist. Currently, tissue biopsy is the main tool to establish a definite diagnosis but is challenged with the limited awareness to suspect HEHE at early stages and the lack of relevant guidelines due to the rarity and the insufficiency of relevant research. The absence of treatment guidelines is the greatest challenge of HEHE. Generally, Surgical approaches are recommended due to the benefits of prolonged survival and enhanced prognosis. Nonetheless, only a minority of patients are eligible for resections while liver transplants are faced with severe insufficiency of donor organs and long wait-lists. On the other hand, a variety of non-surgical treatments (like anti-angiogenic agents, interferon alpha-2B and sirolimus) are presented with a promising potential. However, relevant studies are challenged with limited sample-sizes and lack of prospective designs.

Regardless to decades passing since its discovery, HEHE still creates a dilemma due to its challenging clinical profile and lack of treatment guidelines. Raising awareness of HEHE in clinical practices improves the ability to diagnose this rare tumor at early stages and develop stronger research strategies and treatment guidelines to regulate the medical care provided to HEHE patients.

A variety of chemicals have been linked to occupational liver diseases, including several solvents and mixtures thereof, pesticides, and metals. Workplace exposures have been associated with virtually the entire spectrum of acute and chronic liver diseases. However, their prevalence is inadequately quantified and their epidemiology limited. Occupational liver diseases may result from high accidental or from prolonged lower level exposures. Whereas the former is uncommon and easily recognised, the latter are relatively more frequent but often overlooked because they may display normal values of conventional markers, have an insidious onset and be asymptomatic or be obfuscated and confounded by concurrent conditions. In addition, specific tests of toxicity are not available, histopathology may not be revealing and the assessment of internal dose of chemicals is usually not decisive. Given these circumstances, the diagnosis of these liver disorders is challenging, one of exclusion and often requires an interdisciplinary approach. These recommendations offer a classification of the type of liver injuries associated with occupational exposures - based in part on the criteria for drug-induced liver injury - a grading of their severity, and the diagnostic and preventive criteria for chemically induced occupational liver disease.

To analyze contrast-enhanced ultrasound (CEUS) features of histologically proven hepatic epithelioid hemangioendothelioma (HEHE) in comparison to other multilocular benign focal liver lesions (FLL).

Twenty-five patients with histologically proven HEHE and 45 patients with histologically proven multilocular benign FLL were retrospectively reviewed. Four radiologists assessed the CEUS enhancement pattern in consensus.

HEHE manifested as a single (n = 3) or multinodular (n = 22) FLL. On CEUS, HEHE showed rim-like (18/25, 72%) or heterogeneous hyperenhancement (7/25, 28%) in the arterial phase and hypoenhancement (25/25, 100%) in the portal venous and late phases (PVLP), a sign of malignancy. Eighteen patients showed central unenhanced areas (18/25, 72%); in seven patients (7/25, 28%), more lesions were detected in the PVLP. In contrast, all patients with hemangioma and focal nodular hyperplasia showed hyperenhancement as the most distinctive feature (P < 0.01).

CEUS allows for characterization of unequivocal FLL. By analyzing the hypoenhancement in the PVLP, CEUS can determine the malignant nature of HEHE.

Epithelioid hemangioendotheliomas (EHE) is an extremely rare tumor that can arise not only intracranially but also systemically. Its radiological characteristics and the mechanism underlying the multiple organ involvement in EHE are poorly understood.

A 24-year-old woman with a 7-month history of coughing and blood-stained sputum complained of visual disturbance in the right eye that had persisted for 1-month. Magnetic resonance (MR) imaging revealed multiple intraparenchymal masses with low-intensity on MR susceptibility-weighted images with minimal enhancement with gadolinium. Systemic computed tomography revealed multiple nodules in both lungs and the liver. Because her neurological status rapidly deteriorated, brain biopsy of the right frontal mass was performed. The pathological diagnosis was EHE. Over the following 3 months, the patient gradually developed disturbance of consciousness. She died at 4 months after admission because of significant intracranial hypertension.

Although intracranial EHEs are extremely rare, they should be included in the differential diagnoses of multiple small-sized masses with low-intensity on MR susceptibility-weighted images. We also emphasize that the systemic involvement of this tumor was more compatible with multicentric development than metastasis.

Epithelioid hemangioendothelioma (EHE) of the liver is an extremely rare tumor that masquerades as an epithelial neoplasm and poses significant diagnostic pitfalls for the cytopathologist. This report describes a 64-year-old woman whom on computerized tomography was found to have multiple peripherally calcified hypodense lesions throughout the liver and an ipsilateral adrenal mass. Fine needle aspiration and needle cores biopsies of the largest liver lesion showed epithelioid cells and spindle cells in fibrous stroma. The epithelioid cells had round or oval, hyperchromatic nuclei with smooth nuclear contours, delicate cytoplasm and indistinct cytoplasmic borders. Rare cells had intracellular vascular lumen containing fragmented or intact red blood cells. The cells were individually dispersed or arranged in nests and vague tubular arrays. No mitotic figures or necrosis were seen. An immunohistochemical profile demonstrated diffuse CD31 and focal CD 34 and nuclear Fli-1 immunoexpression and low Ki-67 proliferative activity (1%) within lesional cells confirming the diagnosis of EHE. The differential diagnosis of EHE which includes cholangiocarcinoma, hepatocellular carcinoma, metastatic carcinoma and melanoma is discussed.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor. We report on a patient who underwent hepatectomy for malignant HEH associated with abdominal pain due to rapid progression. An 83-year-old man was admitted to Nippon Medical School Hospital because of acute, severe upper abdominal pain. Seven months before admission, a hepatic tumor, 3 cm in diameter, had been detected in the left lateral sector. The diagnosis was hepatic cavernous hemangioma. Abdominal ultrasonography revealed a heterogeneous hyperechoic tumor with a smooth border, 6 cm in diameter, in the left lateral sector (segment 3). Contrast-enhanced computed tomography of the abdomen showed that the tumor was enhanced from the early to the late phase. Abdominal angiography revealed a cotton wool-like appearance of the tumor. The diagnosis was hepatic cavernous hemangioma. A malignancy could not be ruled out because of the tumor's rapid growth, which had caused abdominal pain. Left hepatectomy was performed. Histopathological examination showed necrosis throughout the tumor. Slightly pleomorphic neoplastic cells with rounded, spindle-like nuclei and scant cytoplasm were sporadically found in vascular channels. Intracytoplasmic lumina occasionally contained red cells. Neoplastic cells were positive for factor VIII-related antigen, CD31, and CD34. The Mib-1 index was high. The tumor was diagnosed as malignant HEH. The postsurgical course was uneventful, and the patient was discharged on postoperative day 11. After 3 months, multiple metastatic tumors appeared in right hepatic lobe. Transcatheter arterial chemoembolization was performed.

Hepatic epithelioid haemangioendothelioma (HEH) is a rare vascular neoplasm with unpredictable clinical behaviour.

To compare overall survival (OS) and disease-free survival (DFS) between liver resection (LR) and orthotopic liver transplantation (OLT) for the treatment of HEH.

Retrospective review of 30 patients with HEH treated at Mayo Clinic during 1984 and 2007.

Median age was 46 years with a female predominance of 2:1. Treatment included LR (n= 11), OLT (n= 11), chemotherapy (n= 5) and no treatment (n= 3). LR was associated with a 1-, 3- and 5-year OS of 100%, 86% and 86% and a DFS of 78%, 62% and 62%, respectively. OLT was associated with a 1-, 3- and 5-year OS of 91%, 73% and 73% and a DFS 64%, 46% and 46%, respectively. Metastases were present in 37% of patients but did not significantly affect OS. Important predictors of a favourable OS and DFS were largest tumour ≤ 10 cm and multifocal disease with ≤ 10 nodules.

LR and OLT achieve comparable results in the treatment of HEH. LR is appropriate for patients with resectable disease and favourable prognostic factors. OLT is appropriate for patients with unresectable disease and possibly those with unfavourable prognostic factors. Metastases may not be a contraindication to surgical treatment.

Orthotopic liver transplantation (OLT) is currently incorporated into the treatment regimens for specific nonhepatocellular malignancies. For patients suffering from early-stage, unresectable hilar cholangiocarcinoma (CCA), OLT preceded by neoadjuvant radiotherapy has the potential to readily achieve a tumor-free margin, accomplish a radical resection, and treat underlying primary sclerosing cholangitis when present. In highly selected stage I and II patients with CCA, the 5-year survival rate is 80%. As additional data are accrued, OLT with neoadjuvant chemoradiation may become a viable alternative to resection for patients with localized, node-negative hilar CCA. Hepatic involvement from neuroendocrine tumors can be treated with OLT when metastases are unresectable or for palliation of medically uncontrollable symptoms. Five-year survival rates as high as 90% have been reported, and the Ki67 labeling index can be used to predict outcomes after OLT. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin. The data from single-institution series are limited, but compiled reviews have reported 1- and 10-year survival rates of 96% and 72%, respectively. Hepatoblastoma is the most common primary hepatic malignancy in children. There exist subtle differences in the timing of chemotherapy between US and European centers; however, the long-term survival rate after transplantation ranges from 66% to 77%. Fibrolamellar hepatocellular carcinoma is a distinct liver malignancy best treated by surgical resection. However, there is an increasing amount of data supporting OLT when resection is contraindicated. In the treatment of either primary or metastatic hepatic sarcomas, unacceptable survival and recurrence rates currently prohibit the use of OLT.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular neoplasm of the liver. Its therapeutic management remains difficult to define in curative intent. The aim of this study was to report long-term results of surgically managed patients.

From 1990 to 2006, nine patients (25-64 years) were retrospectively enrolled in this study. Intrahepatic disease extent was monolobar and bilobar in two and seven patients, respectively. As primary treatment, liver resection (LR) and liver transplantation (LT) were performed in three (two monolobar and one bilobar extent) and six patients, respectively.

Postoperative mortality was nil. During a median follow-up of 117 months, four patients developed intrahepatic and/or extrahepatic recurrence. One resected patient (with bilobar extent) presented with intrahepatic recurrence was secondary treated by LT. At the time of the follow-up, seven out of the nine patients treated (two after LR, and five after LT) were alive and disease-free.

Surgical treatment offers good long-term results in patients suffering from HEHE when LR is tailored to the intrahepatic disease extent: LT has to be considered in patients with bilobar intrahepatic disease whereas LR should be strictly limited to patients presenting with localized and monolobar intrahepatic disease.

Malignant hepatic epithelioid hemangioendothelioma (HEH) is a rare malignant tumor of vascular origin with unknown etiology and a variable natural course. The authors present a comprehensive review of the literature on HEH with a focus on clinical outcome after different therapeutic strategies. All published series on patients with HEH (n = 434 patients) were analyzed from the first description in 1984 to the current literature. The reviewed parameters included demographic data, clinical manifestations, therapeutic modalities, and clinical outcome. The mean age of patients with HEH was 41.7 years, and the male-to-female ratio was 2:3. The most common clinical manifestations were right upper quadrant pain, hepatomegaly, and weight loss. Most patients presented with multifocal tumor that involved both lobes of the liver. Lung, peritoneum, lymph nodes, and bone were the most common sites of extrahepatic involvement at the time of diagnosis. The most common management has been liver transplantation (LTx) (44.8% of patients), followed by no treatment (24.8% of patients), chemotherapy or radiotherapy (21% of patients), and liver resection (LRx) (9.4% of patients). The 1-year and 5-year patient survival rates were 96% and 54.5%, respectively, after LTx; 39.3% and 4.5%, respectively, after no treatment, 73.3% and 30%, respectively, after chemotherapy or radiotherapy; and 100% and 75%, respectively, after LRx. LRx has been the treatment of choice in patients with resectable HEH. However, LTx has been proposed as the treatment of choice because of the hepatic multicentricity of HEH. In addition, LTx is an acceptable option for patients who have HEH with extrahepatic manifestation. Highly selected patients may be able to undergo living-donor LTx, preserving the donor pool. The role of different adjuvant therapies for patients with HEH remains to be determined.

Epithelioid hemangioendothelioma (EH) is a rare tumor of vascular origin, which occurs at sites such as soft tissues, liver, or lung, and has a highly unpredictable malignant potential. It is an intermediate entity between well-differentiated hemangioma and angiosarcoma. We present two cases of this rare disease in which the tumor was detected fortuitously and the definitive diagnosis was based on histological evidence. Both our cases are highly illustrative of the two ways in which hepatic EH can present (nodular or diffuse) and of its diagnostic and therapeutic management. Neoplastic cells expressed the factor VIII-related antigen, CD31 or CD34. Treatment was surgical resection in one patient and liver transplant in the other. Although EH of the liver has a better prognosis than other hepatic neoplasms, conservative treatment is not recommended. Our cases highlight the importance of a histological diagnosis to avoid it being mistaken for another entity.

Epithelioid hemangioendothelioma is a rare vascular tumor with unpredictable behavior. It often presents as liver or lung nodules and is refractory to conventional chemotherapy. Surgical resection and/or liver transplantation have been the mainstay of therapy, but the results are mixed and unsatisfactory. Although the etiology of this malignancy is unknown, an increased incidence in women has been noted, and an association with exposure to vinyl chloride is emerging as a possible risk factor. This review proposes polyurethane/silicone breast implants as a potential cause of the condition and highlights the dramatic response to interferon (IFN)-alpha in a woman, so exposed, with widespread disease in the liver and lungs. The implications for other women who have had this type of implant could be significant, and the early use of IFN-alpha may be optimal.

Epithelioid hemangioendothelioma is an infrequent mesenchymal tumor of unknown etiology and variable clinical symptoms. It usually affects black, middle-aged women. The most frequent symptoms are right hypochondrium pain, abdominal discomfort and constitutional syndrome with progressive liver damage. Diagnosis is difficult and detailed pathological analysis is required. Controlled clinical studies are lacking and there are no factors that predict the clinical course or serve as a guide to the most effective treatment. We report 3 cases with distinct clinical course ranging from clinical stability to dissemination and death. Treatment differed in the three patients.

Hepatic epithelioid haemangioendotheliomas (HEHEs) are rare, low-grade vascular tumours. Five adults with HEHEs and one adult with a vascular tumour showing combined features of haemangioma and haemangioendothelioma underwent liver transplantation. Two HEHE patients had extrahepatic metastases at the time of transplantation. Median survival time following diagnosis was 10.7 years (range 40 months to 195 months). One patient needed resection of a HEHE in the breast 13 years post-transplantation. All six patients are surviving free from disease 22 to 166 months after transplantation (median 77 months). One HEHE-patient who had been treated for 8 years for vertebral and cerebral localisations is free of disease without immunosuppression 56 months after transplantation. We can conclude that liver transplantation is a valuable treatment for hepatic haemangioendothelioma, even in cases of extrahepatic localisation of the disease.

This article focuses on the origin, diagnosis, and management of focal benign lesions of the liver. The most common lesions include cavernous hemangioma, focal nodular hyperplasia, hepatic adenoma, and nodular regenerative hyperplasia. A number of less frequent occurring lesions are also discussed. In general, the common lesions can be diagnosed by radiologic imaging, but occasionally biopsies are required, and surgical removal is often needed.

Primary angiosarcoma of the liver accounts for up to 2% of all primary liver tumors and is the second most common primary malignant neoplasm of the liver. Approximately 10 to 20 new cases are diagnosed every year in the United States and the prevalence varies from 0.14 to 0.25 per million. In an autopsy series from Chicago, one hepatic angiosarcoma was noted for every 30 cases of hepatocellular carcinoma.

Malignant vascular neoplasms of the liver are uncommon. We report the case of a young woman who developed an epithelioid hemangioendothelioma of the liver associated with multiple focal nodular hyperplasias and hepatic cavernous hemangiomas. Such an unusual association is probably not fortuitous and could support the theory that focal nodular hyperplasia is a reaction to an abnormal vascular supply rather than a true neoplasm.

A case of malignant epithelioid hemangioendothelioma of the liver in a 48-year-old woman with severe portal hypertension and marked deformity of the liver is presented. This woman had a history of mild liver dysfunction since the age of 30 years, and abdominal distention, esophageal varices, splenomegaly and ascites since October 1996. Imaging examinations revealed liver deformity with severe atrophy of the left lobe and the anterior segment of the right lobe. Celiac arteriography showed narrowing and upward deviation of the proper hepatic artery, and occlusion of the left and right anterior hepatic arteries. Since March 1997, hepatic venography showed stenosis in the right hepatic vein truncus. Budd-Chiari syndrome was clinically diagnosed. She died in June 1997. The autopsy disclosed massive tumor embolism in the left and right anterior portal branches, few in the hepatic artery, and occlusion of the left and right anterior hepatic arteries. The extensive tumor embolism resulted in portal hypertension, and atrophy of the left lobe. The anterior segment of the right lobe was probably caused by the occlusion of both the hepatic arteries and the portal veins. The posterior segment of the right lobe, without massive tumor embolism in its portal branch, appeared hypertrophic.

Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of vascular origin that occurs in the liver and other organs; its etiology is unknown.

The authors analyzed the clinicopathologic and immunohistochemical features of 137 patients with EHE of the liver in an attempt to identify features that might predict tumor behavior. To their knowledge, this article represents the largest series reported from one institution.

Patients were ages 12-86 years; 84 (61%) were females and 53 (39%) were males. They presented with nonspecific symptoms such as right upper quadrant pain or weight loss. Macroscopically, the tumors usually were multiple. They typically were white, firm to hard, and ranged in size from 0.2-14 cm. Histologically, the tumors were comprised of dendritic and epithelioid cells that often contained vacuoles representing intracellular lumina. The stroma was fibrous, with myxohyaline areas. Immunohistochemically, all tumors were positive for at least one endothelial marker (factor VIII-related antigen [FVIII-RAg], CD34, and/or CD31). Treatment modalities included hepatic resection or transplantation. Although the metastatic rate in this series was 27%, the prognosis is considered much more favorable than that of other hepatic malignancies. Twenty-six patients (43%) survived > or = 5 years; 2 patients were alive and well at last follow-up after 23 and 27 years, respectively. Twenty-six of 60 patients (43%) died of their disease, 1 of whom died 28 years after discovery of her tumor. In an attempt to predict behavior of the tumor, several histologic parameters were evaluated using univariate analysis. No significant correlation was found with mitoses, Glisson's capsule infiltration, or nuclear atypia. High cellularity was significantly correlated with a poor clinical outcome (P = 0.00012), whereas the association with tumor necrosis approached significance (P = 0.057).

EHE is a very rare clinical entity. The key to diagnosis is the demonstration of cells containing FVIII-RAg. The histology of the tumor, including nuclear pleomorphism and the mitotic count, are of no value in predicting clinical outcome. High cellularity most likely is the most significant parameter predicting an unfavorable prognosis in EHE because mitotic counts often are quite low in both low grade and aggressive tumors. Further studies are needed to identify the factors responsible for the apparent dissociation between the clinical behavior and biologic characteristics of this tumor.

A 31 year old female patient presented with a one and a half year history of pain in the upper abdomen. The pain was mild, constant, dull aching, and increased with change in posture or sudden movements. There was no definite relation to meals. She also had a lump in the right upper quadrant, which had been gradually increasing in size over three months. She had mild anorexia and reported a 5 kg weight loss over one year. She had no history of intake of oral contraceptive drugs, exposure to vinyl chloride, thorotrast or any other industrial toxin. Ultrasonography of the abdomen revealed multiple space occupying lesions of altered echotexture in both lobes of the liver. The portal venous system and hepatic vascular system were normal. Computed tomography of the abdomen confirmed the ultrasound findings. Histopathology was diagnostic for primary epithelioid haemangioendothelioma; the first such case reported from India. The patient has been put on a waiting list for a liver transplant.

We present the cytological features of hepatic epithelioid hemangioendothelioma (EH), which is considered to be a vascular proliferation of intermediate malignant potential. The case report concerns a 52-yr-old previously healthy man discovered to have multiple hepatic masses upon evaluation for abnormal liver function tests. Fine-needle aspiration demonstrated a neoplasm composed of interanastomosing epithelioid cells that contained intracytoplasmic lumens. Histologic sections, immunohistochemistry, and ultrastructural evaluation were confirmatory. Although hepatic EH is a rare tumor, its characteristic cytological, histological, and ultrastructural features permit a straightforward diagnosis. It is important to distinguish this entity from adenocarcinoma and angiosarcoma because long-term disease-free survival is possible, especially in the setting of orthotopic liver transplantation.

Epithelioid hemangioendothelioma (EH) is a rare neoplasm of vascular origin that may develop at different sites, such as in soft tissue, the lungs, or the liver. It usually affects adult females, and its unpredictable malignant potential has a range between benign hemangioma and clearly malignant hemangioendotheliosarcoma.

In the current study, the authors describe 2 patients with primary EH of the liver and review 127 previously published cases found in the literature.

Most patients presented with nonspecific symptoms, such as right upper quadrant abdominal pain or weight loss. The tumors usually presented as multiple nodular lesions involving both lobes of the liver. Overall metastasis rate was 45.1%, with preferential involvement of the lungs and bones. In general, the key to diagnosis was the demonstration of cells containing factor-VIII-related antigen.

EH of the liver is a very rare clinical entity. The primary treatments of choice are radical hepatic resection or orthotopic liver transplantation. The 5-year survival of 55.5% is significantly better than for other hepatic malignancies.

Epithelioid hemangioendothelioma is a recently described, rare vasoformative vascular tumor of variable biological behavior. Its principal sites of occurrence are soft tissues, liver, lung, and bone. There have been no formal case reports of this tumor occurring in the vertebral column, and there are no reports in the literature of surgical treatment for vertebral epithelioid hemangioendothelioma. We present a case of primary vertebral epithelioid hemangioendothelioma occurring in the L2 vertebral body. Surgical treatment, pathological findings, imaging characteristics, and a review of the literature are presented.

We report a case of epithelioid haemangioendothelioma involving both lung and liver. The tumour cells were positive for factor-VIII-related antigen. Immunohistochemical analysis of various basement membrane components in tumour tissue of lung and liver showed striking differences. In the liver tumour there was selective expression of collagen IV, with minimal and focal amounts of laminin and basement membrane-associated heparan sulphate proteoglycan. In the lung tumour nodules, in contrast, all these basement membrane components were present. These patterns of basement membrane expression closely resemble those of normal liver and lung basement membrane respectively. We suggest that this provides evidence that epithelioid haemangioendothelioma arises from local endothelial cell proliferation and that it supports the assumption of a multicentric rather than metastatic origin when multiple tumour deposits are found.

Despite considerable overall progress in human liver transplantation the results obtained in patients with malignant tumours have not improved significantly over the past years. One of the crucial questions in the ongoing controversial discussion remains the identification of tumour patients with the most favourable prognosis. In a consecutive series of 114 patients who received hepatic transplants for various malignant tumours of the liver and biliary tract, at least some factors could be shown to play a prognostic role. Regarding the histological type of tumour, fibrolamellar carcinoma, epitheloid haemangioendothelioma, and endocrine hepatic metastases seem to have a better long-term survival, whereas cholangiocellular carcinoma and other liver metastases had the worst outcome. In patients with primary liver or proximal bile duct cancer there was a significant influence of the pathological tumour stage at the time of transplantation: significant palliation or cure was almost essentially restricted to patients with early tumour stages as compared with advanced primary tumours and extrahepatic spread where early tumour recurrence developed in all recipients. Thus, the present concept for the treatment of malignant hepatobiliary tumours should include partial as well as total hepatectomy with subsequent liver replacement. In cases of non-resectable lesions or intrahepatic tumour recurrence following previous resection, liver transplantation offers the only chance for long-term survival.