Epithelioid hemangioendothelioma is a rare neoplasm of vascular origin which can involve the liver (1). Primary involvement of the liver with epithelioid hemangioendothelioma was first reported by Ishak et al. in a series of 32 primary hepatic epithelioid hemangioendotheliomas (HEH) (2). HEH has also been observed in other visceral organs (3,4). The clinicopathological course of HEH ranges between benign hemangioma and angiosarcoma (1,3). HEH usually affects adult females and is characterized by an epithelioid or histiocytoid morphology and a growth pattern with evidence of endothelial histogenesis (4). Its vascular nature is supported by the detection of a positive staining for factor VIII-related antigen and specifically the so-called Weibel-Palade bodies. Immunohistochemical identification of factor VIII-related antigen is essential to distinguish HEH from metastatic carcinoma or primary liver tumors (4). For curative therapy, liver resection (LRx) or liver transplantation (LTx) have been implemented. Because of the rarity of HEH and its variable natural history, the effectiveness of both methods currently cannot be finally defined. In this paper, we present our single-center experience with respect to the surgical treatment of four patients with HEH.
Between 1992 and 2003, four adult patients with primary HEH were surgically treated with LTx or LRx in our department. Patient data are provided in Table 1. One patient with primary HEH without extrahepatic manifestation was listed for LTx. Unfortunately, the patient died after 2 months on the waiting list due to severe liver failure caused by extensive tumor progression.
Demographic Data and Clinical Manifestations
All patients were female with a mean age of 39 years (range 32–61 years). Right upper quadrant abdominal pain was the main presenting symptom (three cases). Weight loss and weakness were major manifestations in one patient. Hepatomegaly and a palpable epigastric mass were observed in two patients and one patient was completely asymptomatic. In this setting, HEH was detected during a routine examination. In four patients, an increase of alkaline phosphatase was the most dominant laboratory finding. Two patients showed laboratory results of cholestasis with increased gamma-glutamyl transpeptidase and bilirubin levels.
Ultrasonography, as the first-line diagnostic method, showed abnormal findings in all patients. Multifocal lesions with heterogeneous echogenicity in different tumor sizes were detected. Extrahepatic involvement was ruled out by esophagogastroscopy and colonoscopy, followed by computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen. In all five patients, multiple nodular lesions were encountered, which showed typical nodular HEH with a peripheral enhancement of contrast medium and hypovascularized central lesions. A liver capsule retraction in two cases and hepatic parenchymal calcifications in one case could be seen. In one case, there was a pronounced compensatory hypertrophy of the left lateral liver segment, which was not involved. Portal hypertension and splenomegaly were not evident in our patients. The histopathological diagnosis of HEH was confirmed by needle biopsy in all patients.
Surgical Treatment and Follow-up
One patient died after 2 months on the waiting list for LTx, before surgical intervention could be achieved. In two patients, cadaveric LTx was performed. In one of the transplant patients, preoperative transarterial chemoembolization (TACE) was performed to control tumor progression and bridge the waiting time. Due to rapid tumor progression, a living related liver LTx was performed on one patient. Another patient underwent a right hemihepatectomy with partial resection of the diaphragm. All patients were regularly seen in our outpatient clinics, with follow-up periods ranging from 1 to 13 years. No adjuvant or neoadjuvant radiotherapy, immunotherapy, or chemotherapy was employed. Until now, no tumor recurrences or metastases were observed (Table 1).
HEH occurs more commonly in women, with a female-to-male ratio of 3:2 (4). Correspondingly, all of our patients were females. The reported average age in a literature review of 137 patients with HEH was 46.8 years (range 12–86 years). It can be stated that the average age of patients with HEH at the time of diagnosis is lower compared to patients with other hepatic malignancies (1,5). Although some factors are assumed to play a role in the etiology of HEH, its etiology is still unknown. The clinical manifestation of HEH is heterogeneous and varies between asymptomatic patients to cases with portal hypertension (6) or hepatic failure because of hepatic vessel infiltration and ischemia. At the time of diagnosis, about 42% of the patients are asymptomatic (1). Clinical symptoms are unspecific. The most frequent symptom noted in the literature has been right upper quadrant pain followed by weight loss, jaundice, and general fatigue (1,4). Certain features can point to the diagnosis of HEH: the occurrence of a liver tumor in young adults, particularly the presence of numerous intrahepatic tumors associated with good clinical condition of the patient, a slow growth pattern, and the presence of intratumoral calcifications (7). Increased levels of serum alkaline phosphatase were shown in 70% of patients with HEH (4). Tumor markers (AFP, CEA, CA 19-9) usually are within normal range (4). Laboratory findings thus far are of no help for the diagnosis of HEH.
Besides an intrahepatic tumor presentation, the most common presentations in radiological investigations include hepatomegaly (46%), splenomegaly (17%), ascites (13%), and portal hypertension (5%) (4). Two different types of hepatic HEH, which could be considered different tumor stages, have been described: the nodular type, which represents an early stage of HEH, and the diffuse type, possibly reflecting an advanced stage of the disease associated with vascular invasion of hepatic and/or portal veins (7,8). HEH may appear as discrete nodules ranging from 0.5 to 12 cm in diameter or as complex confluent masses with a tendency to coalesce (9,10). A multifocal nodular pattern of infiltration is often observed in the early stage. Later, lesions can increase in size and coalesce, forming a more diffuse infiltration pattern (9,10). Many lesions are peripheral in location and extend to the liver capsule. Flattening or capsular retraction of the liver capsule due to fibrosis and compensatory hypertrophy of the unaffected liver segments may be diagnostic clues (10,11). On ultrasonography, the echogenicity of individual lesions is variable. Most lesions are hypoechoic to adjacent hepatic parenchyma (9,10). Although the nodular type of HEH has a rather nonspecific appearance in the CT or MR scan, the diffuse type is very suggestive of HEH if the following criteria are fulfilled: a large, slow growing tumor of the liver, mainly located in the hepatic periphery without bulging of the liver capsule; peripheral enhancement of contrast; hypervascularized central lesions; a tendency of the tumor nodules to merge into each other; compensatory hypertrophy of liver segments that are not affected; signs of portal hypertension; splenomegaly; and local calcifications (4,9,12,13,14). A retraction of the adjacent liver capsule may occur in less than 25% of the patients due to lesion-related fibrosis (10,14,15). Hepatic parenchymal calcification may be seen (9,10). HEH is usually hypointese on T1-weighted and hyperintense on T2-weighted images (10,16).
The definitive diagnosis can only be made by histopathalogical investigation (2,7,17–19). Microscopically, HEH is characterized by medium- to large-sized cells that are epithelioid in appearance. These cells typically spread within sinusoids and small veins, forming cell clusters (4). The diagnosis is confirmed with immunohistochemical evidence of an endothelial type of tumor differentiation, as demonstrated by the presence of factor VIII-related antigen and cytokeratins (7). There is often a characteristic vascular invasion with the tufting of portal vein branches and terminal hepatic venules; the identification of epithelioid and positive dendritic cells for endothelial markers (FVIII-related antigen, CD34, and CD31); the negative staining for mucin, bile, CEA, or α-fetoprotein; and the characteristic ultrastructural features such as investing basal lamina, cytoplasmic intermediate filaments, Weibel-Palade bodies, and pinocytotic vesicles (2). Two main histologic features typically characterize HEH: The presence of the characteristic dendritic and/or epithelioid cells with evidence of vascular differentiation and identification of intracytoplasmic lumina containing red blood cells The presence of the stroma, which varies from myxomatous to densely fibrotic. Variable degrees of fibrosis are also observed in all HEH tumors (1). Tumor-associated fibrogenesis may limit tumor growth and could account for the long-term survival of many patients (2). Spontaneous regression of the lesions has been reported in 4 of 137 cases. Most common differential diagnoses were cholangiocarcinoma, angiosarcoma, hepatocellular carcinoma, liver metastases, and sclerosing liver hemangioma (1).
In the literature, the overall rate of HEH metastases at the time point of diagnosis was 45%. Lungs, bones and spleen are the most frequently reported localizations of HEH metastases (4). Different surgical and nonsurgical treatment options for HEH have been used so far, such as LRx, LTx, chemotherapy, radiotherapy, hormone therapy, thermoablation, percutaneous ethanol injection therapy (20). Because of the rarity of HEH, the explicit roles of these treatment modalities currently cannot be established. Interestingly, some reports even state a long survival of patients without any specific treatment (1). Nevertheless, rapid tumor progression can also be encountered. For example, one patient in our study died while on the waiting list for LTx due to rapid progression and subsequent liver failure. In the majority of cases, the multicentricity of HEH lesions renders a curative liver resection technically impossible (1). Correspondingly, overall results after non-curative LRx have been rather disappointing in the literature thus far (21). Increased tumor aggressiveness and growth speed after resection have even been encountered in some cases. This may be caused by an increased HEH tumor sensitivity to hepatotrophic growth factors. Some authors therefore hesitate to perform resection for apparently resectable cases of HEH (21). On the other hand, metastatic spread at the time of surgery does not correlate to survival and has not been considered a contraindication to surgery (1,18,19). Our patient, who underwent LRx thus far, has shown no tumor recurrence of the disease after a rather long follow-up period of 6 years.
In recent years, most HEH patients were treated by LTx in currently reported series. A prolonged disease-free survival after LTx has been described. Life expectancy for patients with HEH could be extended significantly; therefore, even limited extrahepatic disease should not be considered as an absolute contraindication to LTx according to some authors (21,22). Indeed, cadaveric LTx was also performed in two of our patients with a disease free follow-up period of 1 and 13 years. On the other hand, it has to be stated that some patients with intrahepatic HEH have developed rapid tumor recurrence and extrahepatic metastases after LTx (21,27). Because of gross organ shortages some authors have suggested living donor LTx for treatment of HEH (23). One patient in our study underwent a living related LTx (left hemiliver) in the instance of rapid intrahepatic tumor progression. Because the course of HEH is not predictable in the individual patient, LTx could be even more aggressively considered as a potential treatment for patients with HEH. Correspondingly, in a recent review, early LTx was advocated in most patients with HEH. It could be shown that LTx is indeed a valuable treatment even in extrahepatic disease (22).
Extrahepatic tumor spread does not appear to influence the prognosis of HEH patients (7). The natural course and the prognosis are unpredictable and there is also no proven correlation between the morphological grading or clinical staging and outcome (2,3,21). On average, HEH is characterized by a protracted, relatively benign clinical course, intermediate between benign hemangioendothelioma and malignant hemangioendotheliosarcoma (4). A limited number of clinical series describing HEH treatment has been reported in the literature. The recurrence rate in a series of 11 patients was 27% for patients who underwent very different treatment methods (21). In another clinical series, the overall 5-year survival rate of HEH was reported as 55.5%, again for different treatment modalities or simple observation (4). Madariaga et al. reported 1- and 5-year patient survival rates of 100% and 71.3%, respectively. In a survey of 16 patients after LTx 1- and 5-year disease-free survivals were observed in 81.3% and 60.2%, respectively (17). Yokoyama et al. have reported 1- and 5-year survival rates of 88% and 48% in eight patients treated by LTx (27). Seven of the 21 patients in the series of Penn et al. developed HEH recurrences, where there was a 5-year posttransplantation survival rate of 43% (28). Medical treatment still has no proven role in the treatment of HEH. Systemic chemotherapy has thus far been mostly ineffective (2,24,25). Interferon alpha-2b has been used to control metastatic growth of HEH after LTx in a selected case (26). Although it resulted in substantial regression of the metastases and alleviation of clinical symptoms, the patient died of graft rejection and its complications. Interferon therapy prior to LTx is also discussed as an option to slow tumor growth (26).
In conclusion, the therapeutic algorithm for HEH currently is difficult to define. Tumor dignity and prognosis of HEH in individual patients are always unclear. There is still much controversy concerning the effectiveness of the different surgical options currently available. Nevertheless, in most reports surgical resection of HEH or LTx were described to be the most reasonable therapeutic approach. In our series, we could also demonstrate that HEH patients without extrahepatic manifestations can have a long-term survival when they are treated by LTx. In cases of acute tumor progression, living related LTx could play an important therapeutic role in future series. Only long-term follow-up of patients will help evaluate the different surgical options. A worldwide registry of HEH cases is required to gain better data and evidence concerning the optimal therapeutic strategy of this rare disease.
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