Primary malignant hepatic epithelioid hemangioendothelioma

A comprehensive review of the literature with emphasis on the surgical therapy

Authors


Abstract

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. Cancer 2006. © 2006 American Cancer Society

Epithelioid hemangioendothelioma (EH) is a rare neoplasm of vascular origin that involves soft tissue and visceral organs.1 The term EH was defined as a distinct entity first by Weiss and Enzinger in 1982 as a soft tissue vascular tumor of endothelial origin with a clinical course between benign hemangioma and angiosarcoma.1, 2 A similar tumor in lung was described originally by Dail and Liebow in 1975 that was considered to be of epithelial origin and was named “intravascular bronchioalveolar tumor” (IVBAT).3 Corrin et al. first recognized the angiogenic nature of IVBAT based on the identification of Weibel–Palade bodies.4 Other proposed terms for this tumor included sclerosing endothelial tumor, sclerosing angiogenic tumor, sclerosing epithelioid angiosarcoma, and sclerosing interstitial vascular sarcoma5; however, currently, none of those names are used. Primary malignant hepatic EH (HEH) is a rare tumor with an incidence of <0.1 per 100,000 population6 that was reported first in 1984 by Ishak et al. in a series of 32 patients.5 Since then, EH has been described in other organs, including spleen, bone, brain, meninges, breast, heart, head and neck, soft tissue, stomach, and lymph nodes.2, 7–11 The characteristics of primary EH in some important sites are shown in Table 1. HEH more commonly affects adult females and is characterized by an epithelioid or histiocytoid morphology and a growth pattern with evidence of endothelial histogenesis.12 Its vascular nature is confirmed by positive staining for factor VIII-related antigen and other endothelial cell markers (CD31, CD34) in addition to the ultrastructural characteristics of well developed basal lamina, pinocytotic vesicles, and, more specifically, Weibel–Palade bodies. Immunohistochemical identification of factor VIII-related antigen is helpful in differentiating between metastatic carcinoma and primary epithelial liver tumors.12 From the therapeutic aspect, liver resection (LRx), liver transplantation (LTx), chemotherapy, radiotherapy, and/or immunotherapy have been used in the treatment of patients with HEH; however, because of the rarity of this tumor and its unpredictable natural history, it is impossible to assess the effectiveness of these respective therapies. In this report, our objective was to review the literature on the basis of clinical aspects and diagnostic options, different therapeutic modalities, and the clinical outcome of all previously reported patients with HEH.

Table 1. Comparison of Epithelioid Hemangioendothelioma in Different Sites*
OrganAgeGenderDistributionAngiocentricityMortality (%)
  • M indicates male; F, female.

  • *

    This table shows that the majority of primary epithelioid hemangioendothelioma (EH) arises from soft tissue, bone, lung, and liver. The worst outcome was observed among patients with EH in the lung followed by those with hepatic EH. There was a difference noted with regard to age and gender for various EH sites.8, 98–101

Soft tissueSecond to 9th decadeM ∼ FInitially solitary, rarely multifocal50% arise from vessel˜20
BoneSecond to 8th decade; peak mid-adult life 3d/4th decadeM ≫ F>60% multifocal?low, indolent course
LungSecond to 6th decade median, 40 yF > M (4:1)>50% multifocalIntravascular spread common>65
LiverSecond to 9th decadeF > M (2:1)>50% multifocalIntravascular spread common>65

Review of the Literature

In this survey, published reports of 434 patients with HEH in the literature (MEDLINE) were evaluated, including 32 repetitive patients. The data presented in some articles were insufficient to distinguish all repetitive patients. The first reports were mainly histopathologic-based. Over the last decade, authors paid more attention to defining the radiologic, surgical, and therapeutic aspects of this entity. We reviewed data regarding 402 patients with HEH who were reported from 1984 to 2005 (Table 2). Based on the given data in the reviewed literature, all patients had primary HEH, and patients with secondary HEH were omitted from this review. All patients were analyzed according to gender, age, clinical manifestations, diagnostic tools, histopathologic aspects, therapeutic strategies, and clinical outcome.

Table 2. Patients Evaluated for Hepatic Epithelioid Hemangioendothelioma from 1984 to 2005*
ReferenceNo. of patients
  • *

    The year of publication and the number of patients in the study are shown. In total, there were 434 patients. By subtracting 32 duplicate patients, 402 patients remained and were the basis of the current review.

Ishak et al., 1984532
Fukayama et al., 1984211
Dean et al., 1985135
Eckstein and Ravich, 1986592
Ekfors et al., 1986601
Forbes et al., 1987613
Kawabe et al. 1987621
Noguchi et al., 1987631
Cobden et al., 1988642
Darras et al., 1988141
Marino et al., 19884410
Radin et al., 1988224
Scozec et al., 1988655
Bellmunt et al., 1989661
Dietze et al., 19893312
Furui et al., 1989235
Gambacorta and Bonacina, 1989521
Holley and Cuschieri, 1989531
Kelleher et al., 19893110
Lee et al., 1989671
Terada et al., 1989181
Gelin et al., 1989681
Yokoyama et al., 1990578
Penn, 19914021
Shin et al., 1991691
Fedeli et al., 1991552
Banerjee and Rennison, 1992171
Miller et al., 19922513
Yoshikawa et al., 1992701
Van Beers et al., 1992275
Furuta et al., 1992711
Ohtomo et al., 1992721
Morris et al., 1993502
de Man et al., 1994151
Pichlmayr et al., 1994467
Hidaka et al., 1995731
Rojter et al., 1995741
Madariaga et al., 19954516
Lauffer et al., 1996122
Cho et al., 1997751
Gianni et al., 1997301
Idilman et al., 1997511
Soslow et al., 1997161
Sansonno et al., 1997761
Den Bakker et al., 1998771
Walsh et al., 1998781
Peterson et al., 1998796
Hung et al., 1998561
Ben-Haim et al., 19994311
Bralet et al., 1999801
Hayashi et al., 1999191
Sans et al., 1999811
Ros et al., 1999281
Shen et al., 1999821
Makhlouf et al., 19991137
Taege et al., 1999341
Kehagias et al., 2000292
Nagase et al., 2000831
Mendlick et al., 2001841
Uchimura et al., 20018534
Blachar et al., 2002861
D'Annibale et al., 2002201
Goyal et al., 2002871
Imanishi et al., 2002881
Kayler et al., 2002541
Leonardou et al., 2002491
Elias and Ryan, 2003891
Simpson et al., 2003471
St Peter et al., 2003901
Almogy et al., 2004911
Mermuys et al., 2004921
Sotiropoulos et al., 2004391
Lerut et al., 2004416
Kim et al., 2004351
Dighe et al., 2004933
Mascarenhas et al., 2005941
Woller et al., 2005951
Frider et al., 2005961
Haydon et al., 2005976
Langrehr et al., 2005377
Mehrabi et al., 2005425

Demographic data and clinical manifestations

From 402 analyzed patients, the gender of 363 patients was documented: Thus, 154 of 402 patients were men (42.4%), and 209 of 402 patients were women (57.6%; male-to-female ratio, 2:3). The mean age in 327 patients was 41.7 years (range, 3–86 years). An analysis of all reported patients indicated that the clinical manifestation of HEH was heterogeneous and varied from asymptomatic patients to patients with portal hypertension or hepatic failure. The presenting signs and symptoms were available in 294 patients (Table 3). At the time of diagnosis, 25% of reported patients were asymptomatic. Among symptomatic patients, the most common clinical manifestations were right upper quadrant pain (48.6%), hepatomegaly (20.4%), and weight loss (15.6%). Weakness, anorexia, epigastric mass, ascites, nausea/emesis, jaundice, and fatigue were the next most common presenting manifestations (Table 3). The involved liver lobes were reported in 306 patients: Eighty-seven percent of patients presented with a multifocal tumor that involved both liver lobes (Fig. 1a), whereas only 13% of the patients had a unifocal tumor (Table 4). The right lobe was affected more than the left lobe in both multifocal and unifocal presentations. Extrahepatic involvement at the time of diagnosis was observed only in 36.6% of patients (90 of 246 patients with enough data for the analysis). The lungs (8.5%), regional lymph nodes (7.7%), peritoneum (6.1%), bone (4.9%), spleen (3.2%), and diaphragm (1.6%) were the most common sites of extrahepatic involvement at the time of diagnosis (Table 5). Pleura, mediastinum, retroperitoneum, myocardium, pericardium, brain, cervical lymph nodes, common bile duct, pancreas, and uterus were the other reported sites with HEH metastases.

Figure 1.

These photomicrographs show sections of malignant hepatic hemangioendothelioma. (a) Macroscopy shows a multifocal growth pattern of nodules and the coalescence of nodules to form variable-sized, confluent masses in both lobes of the liver, specifically in the periphery with extension to and retraction of the Glisson capsule. (b) In this hematoxylin and eosin-stained section, tumor cells form intracytoplasmic lumina that contain erythrocytes. (c) This tissue was stained for factor VIII-related antigen: In addition to the intracytoplasmic lumens, the pleomorphic cells of hepatic epithelioid hemangioendothelioma are immunoreactive for factor VIII-related Ag in this tissue section.

Table 3. Presenting Signs and Symptoms of the Patients with Hepatic Epithelioid Hemangioendothelioma*
Presenting signs and symptoms (n = 294)No. of patients%
  • RUQ indicates right upper quadrant.

  • *

    In 294 patients, the clinical manifestations were described in sufficient detail, whereas the reports for 108 patients contained no adequate information. Some patients may have shown >1 sign or symptom.

Asymptomatic7324.8
RUQ pain14348.6
Hepatomegaly6020.4
Weight loss4615.6
Weakness248.2
Anorexia248.2
Epigastric mass227.5
Ascites206.8
Nausea/emesis206.8
Jaundice196.5
Fatigability186.1
Abdominal fullness/discomfort165.4
Fever134.4
Splenomegaly72.4
Chest pain/shoulder pain/costal arch pain62
Malaise51.7
Abdominal tenderness31
Cough/dyspnea31
Cirrhosis31
Others206.8
Table 4. Mode (Multifocal or Unifocal) and Side of Liver Involvement (n = 306 Evaluable Patients)*
Side of involvementNo. of patients%
  • *

    The numbers and percentages of patients in each subgroup are shown.

Multifocal involvement (87.3%)
 Right and left24881
 Right165.2
 Left31
Unifocal involvement (12.7%)
 Right258.2
 Left31
 Right or left113.6
Table 5. Location of Pretreatment Extrahepatic Manifestation in Patients with Epithelioid Hemangioendothelioma (n = 246 Evaluable Patients)*
Pretreatment extrahepatic manifestation (n = 246)No. of patients%
  • *

    Of 246 patients who were evaluable, 90 patients (36.6%) demonstrated extrahepatic manifestations. The distribution of these manifestations is shown according to location. Some patients had >1 site of extrahepatic involvement.

Without involvement15663.3
Lung218.5
Regional lymph nodes197.7
Peritoneum-omentum156.1
Bone124.9
Spleen83.2
Diaphragm41.6
Pleura20.8
Mediastinum20.8
Retroperitoneum20.8
Others72.8
Unknown249.7

Etiopathogenetic factors

Some possible etiologic factors of HEH include oral contraceptives,13 vinyl chloride,14 asbestos,15 thorotrast,16 major trauma to the liver,17 viral hepatitis,1, 12 primary biliary cirrhosis,18 and alcohol consumption.1 HEH, in contrast to many other types of primary liver tumor, does not arise in a background of chronic liver disease, as described previously.12, 19, 20 Based on current knowledge, no definitive etiology has been confirmed as a causative factor for HEH.

Approach to Diagnosis

Laboratory parameters

The laboratory data on 185 patients were available and indicated that 156 patients (84.3%) had abnormal findings and that 15.7% of patients did not show any abnormality. With regard to laboratory parameters, increased alkaline phosphatase (68.6%), γ-glutamyl transpeptidase (45.1%), aspartate aminotransferase (28.6%), alanine aminotransferase (23%), and bilirubin (19.9%) levels were the most prominent abnormal changes. Most tumor markers (e.g., α-fetoprotein, carcinoembryonic antigen, and CA 19-9) were in the normal range and, in the current context, were suitable only for ruling out other primary or metastatic liver tumors.

Imaging and diagnostic tools

The results of imaging studies are not suggestive for vascular tumors; in fact, they are more consistent with a diagnosis of metastatic carcinoma.20 Two different types of HEH with different stages have been described: 1) the nodular type in the early stage of HEH and 2) the diffuse type, which reflects advanced-stage disease because of an increase in size and coalescence of the lesions often associated with hepatic vascular invasion.20–23 At least 1 imaging study was obtained in 168 patients; whereas, in 218 patients, no diagnostic imaging studies were reported, because those articles did not focus on imaging diagnosis. HEH may appear as discrete nodules ranging in dimension from 0.5 cm to 12 cm or as complex, confluent masses with a tendency to coalesce.22, 24 Many lesions are peripheral and extend to the liver capsule. Flattening or retraction of the liver capsule because of fibrosis and compensatory hypertrophy of the unaffected liver segments may be diagnostic clues.19, 24

On ultrasonography, either discrete nodules or diffusely echotexture regions with extensive liver involvement may be seen.22, 25 Ultrasonographic data were available for 103 patients, including 80 patients who had information regarding the echogenicity of the tumors. On ultrasonography, most frequently, the lesions are hypoechoic relative to the adjacent hepatic parenchyma.22, 24 In the reported patients, the hypoechoic pattern was the most common type of echogenicity (n = 53 patients; 66.3%). The other patterns of echogenicity included heterogeneous (n = 18 patients; 22.5%), hyperechoic (n = 5 patients; 6.2%), and isoechoic with hypoechoic rim (n = 4 patients; 5%). Radin et al. demonstrated that there was no correlation between echogenicity and tumor size.22 Calcifications within the nodules were recognizable in 6 patients. Splenomegaly and capsular retraction were observed in 6 patients and 1 patient, respectively. Normal ultrasonography was reported in 3 patients (3%).

Of 142 patients who had computed tomography (CT) scans available, 104 patients had information available on density pattern. Low-density pattern was the most common abnormal feature and was reported in 102 patients (98%). High-density and heterogeneous mixed-density lesions each accounted for 1% of CT scan findings. Additional findings included calcifications (12.7%), capsular retraction (10.6%), splenomegaly (3.5%), compensatory hypertrophy (3.5%), and cystic lesions (1.4%). It is noteworthy that normal CT scans were reported in 2 patients (1.4%). CT scanning has greater sensitivity for detecting calcification compared with ultrasonography. Generally, in CT scans of HEH, 2 major manifestations may be seen: multiple, nodular lesions and/or large masses that, some have speculated, are a result of the coalescence of smaller nodules.26 The nodular type is relatively nonspecific, whereas the diffuse type is very suggestive on the CT scan if the following criteria are fulfilled: 1) large and slow-growing tumor, mainly located in the periphery, without actual bulging of the liver capsule because of its fibrotic structures; 2) peripheral enhancement of contrast medium and the demonstration of many hypervascularized, central lesions with a tendency for the tumor nodules to merge into each other and no traceable sign of the portal or hepatic veins in the CT scan; and 3) pronounced, compensatory hypertrophy of the unaffected liver segments, portal hypertension and splenomegaly, and local calcifications.23, 25–27 In 61 patients, information was available on enhancement pattern. The majority of patients had enhancement (76%), whereas “no enhancement” (20.6%) and “variable, irregular enhancement” (3.4%) were the other reported patterns. Patients with HEH show both peripheral and central enhancements on CT scans.26 Because, on contrast-enhanced scans, tumor nodules may become isodense to liver parenchyma, the extent of involvement may be defined better on unenhanced images.24 Retraction of the adjacent liver capsule is likely caused by lesion-related fibrosis.25

Magnetic resonance imaging (MRI) studies of the abdomen were available for 48 patients. On T1-weighted images, low signal intensity (89%), low signal intensity with a peripheral dark rim (7%), and isosignal intensity with a peripheral dark rim (4%) were reported. On T2-weighted images, high signal intensity (48.5%) was the most frequent signal feature, followed by mixed signal intensity with a peripheral dark rim (29%), high signal intensity with a peripheral dark rim (16%), and central low signal intensity with a peripheral high-signal rim (6.5%). Other MRI findings included capsular retraction and flattening (12.5%), hepatomegaly (8.3%), portal branch invasion (4%), hepatic vein narrowing or obliteration (4%), inferior vena cava compression (4%), and collateral vessels (2%). MRI studies with gadolinium contrast were obtained in 16 patients and resulted in high enhancement (37.5%), peripheral and delayed central enhancement (37.5%), concentric layers of variable intensity (19%), and no enhancement (6%). In conclusion, HEH usually is hypointense on T1-weighted images and hyperintense on T2-weighted images (Fig. 2a-c). The target appearance of the lesions may be caused by the presence of a central sclerotic zone and a peripheral region of cellular proliferation (Fig. 2c).28 Central low-signal areas may correspond to hemorrhage, coagulation necrosis, and calcification; whereas peripheral high signal intensity corresponds to edematous connective tissue and viable tumor.29 After intravenous administration of gadopentetate dimeglumine, peripheral enhancement occurs with a thin, unenhanced rim that reflects a narrow, avascular zone between normal liver parenchyma and the nodules.24, 29 Ferumoxides-enhanced, T1-weighted images can define the extent of tumor more clearly than other images29; however, the distinction between normal liver parenchyma and tumor may be difficult on some sequences. Dynamic MRI studies in 1 patient revealed faint enhancement in late phase.

Figure 2.

These magnetic resonance images (MRIs) show sections of hepatic epithelioid hemangioendothelioma (HEH). (a) This T1-weighted MRI of the liver shows typical, multiple, hypointense lesions with necrosis. (b) This contrast-enhanced, T1-weighted MRI of the liver shows reduced enhancement of the lesions and central necrosis. (c) This T2-weighted image shows hyperintense lesions and central necrosis with a target appearance.

Scintigraphic imaging techniques with 99mTc, gallium-67, and indium-leukocyte also have been used in the diagnosis of HEH. In our reviewed series, among 18 scintigraphic imaging studies, 78% demonstrated low uptake. On scintigraphy, decreased perfusion of involved areas may be observed with increased blood flow to uninvolved areas.22 Some investigators have postulated that tumor growth within portal vein branches can cause blood shunt and, consequently, a reduction in flow rate.22, 24 Red blood cell scintigraphy studies were obtained in 1 patient and showed increased signal. Gianni et al. used 2 complementary methods to define HEH better, including blood pool imaging with labeled red blood cells (positive images) and the use of 99mTc phytate as a label for negative images.30 These substances are very helpful in patients who have contraindications for the use of iodine radiomarkers in CT scans. Moreover, scintigraphic imaging may have an important role in the staging of patients who undergo LRx or especially LTx.30

In the past, angiographic examination of the liver was performed only in selected patients and revealed only moderate vascularization. In our review, 56 patients had angiographic studies obtained, and the findings were completely heterogeneous, ranging from hypo- to hyperperfusion.

The other diagnostic tools mentioned in some articles included plain abdomen studies (n = 32 patients), in which calcification (72%), elevated diaphragm (3%), and mass (3%) were the most important findings, and endoscopic retrograde cholangiopancreatography (n = 8 patients), which demonstrated biliary abnormalities (25%) or a normal pattern (75%). Three patients underwent diagnostic laparoscopy, and showed multiple tumors in 1 patient with peritoneal tumor spread.

It is important to mention that imaging studies cannot provide a definite diagnosis and only can lead to a strong suspicion regarding the presence of HEH and its pattern. Generally, in the nodular form, a specific diagnosis is impossible without performing a biopsy, because the radiologic findings are similar to those in some hepatic metastases. The diffuse form of HEH seems to present somewhat more specific diagnostic criteria, although differentiation from cholangiocarcinoma, hepatocellular carcinoma, some metastases, and venooclusive hepatic disease can be difficult.28 The definitive diagnosis requires a histopathologic analysis. Positive imaging findings in addition to certain features, such as occurrence in younger adults, the presence of numerous intrahepatic tumors with a good clinical condition, slow course of the disease, and the presence of intratumoral calcifications, are suggestive for HEH.20, 27

Histopathologic aspects

A definitive diagnosis of HEH requires histopathologic examination. Often, a laparoscopic wedge or core biopsy is sufficient to encompass the architectural features of HEH, such as the intravascular characteristics.5, 31, 32 Because of a lack of information concerning the frequency of image-guided core biopsy performed for diagnosis, a precise statement about this type of biopsy cannot be made. However, in a study by Makhlouf et al. of 137 patients, the diagnostic modalities included wedge biopsy (46%), core needle biopsy (22%), core needle and wedge biopsy (20%), autopsy (7%), liver resection (3%), and total hepatectomy (2%).1 The diagnosis mostly is confirmed by immunohistochemical evidence of endothelial differentiation (Fig. 1b), as demonstrated by the presence of factor VIII-related antigen (in nearly all patients) (Fig. 1c), the presence of CD34 (94%), and CD31 (86%).20 The immunohistochemistry features are described in detail in the literature.1, 12, 33–36

It should be pointed out that, despite the necessity of laparotomy or laparoscopy for wedge biopsy and the risk of peritoneal seeding, no reported data were found in the literature regarding the sarcomatosis propensity after peritoneal spillage. Furthermore, the articles that were reviewed did not provide any information regarding the sensitivity or specificity of core biopsy. This lack may be because of the rarity of the tumor and because it is hard to differentiate from sclerosing adenocarcinoma. In addition, missing diagnostic biopsies (necessitating controlled autopsy studies) as well as the quality and case load of the institute are other important factors that should be taken into account. However, HEH is diagnosed well with core biopsy if the tumor is targeted precisely and if the pathologist is experienced in the entity. However, core biopsy can be confused, particularly with sclerosing hemangioma and sclerosing adenocarcinoma (e.g., cholangiocarcinoma), but not with angiosarcoma. The histology, in conjunction with the immunohistology, provides a valuable diagnosis. Theoretically, in patients with HEH, the specificity of the diagnosis is quite high either with a “good” biopsy specimen or with a resection specimen.

Differential diagnosis

Because of the variable patterns of the tumor, which may mimic other lesions, the pathologist's awareness is essential.12 Approximately 60% to 80% of patients with HEH initially were misdiagnosed.1, 36, 37 The most common misdiagnoses were cholangiocarcinoma, angiosarcoma, hepatocellular carcinoma (HCC), metastatic carcinoma, and sclerosing hemangioma.1 Mixed hamartoma, spindle cell neoplasm, inflammatory pseudotumors, bile duct adenoma, cirrhosis, carcinoma with chondromyxoid change, venooclusive disease, fibrolamellar carcinoma, postnecrotic fibrosis, and Budd–Chiari syndrome were less common misdiagnoses.1, 5, 38 Some important features for differential diagnosis include the infiltrative growth pattern with preservation of the hepatic acinar landmarks, such as portal areas; the characteristic vascular invasion with tufting of portal vein branches and terminal hepatic venules; the identification of epithelioid and dendritic tumor cells, especially with intracytoplasmic lumina (Fig. 1b); and the delay of staining for epithelial differentiation markers, especially cytokeratins. If 1 or several of these aspects are present, then HEH should be considered5 (Table 6).

Table 6. The Differential Diagnosis of Hepatic Epithelioid Hemangioendothelioma Based on Histopathologic Features*
Histopathologic featureMalignant HEHAngiosarcoma(Sclerosing) Adenocarcinoma
  • HEH indicates hepatic epithelioid hemangioendothelioma; 0, absent; +, few; ++, moderate; +++, prominent.

  • *

    The major difference between malignant HEH and angiosarcoma was the greater tendency of the angiosarcoma to have a destructive growth pattern. Malignant HEH preserved the portal tracts more than angiosarcoma and sclerosing adenocarcinoma.

Preservation of portal tracts++(+)(+)
Intracellular lumina+00
Vascular invasion+++++++
Destructive growth++++++
Endothelial markers++0
Cytokeratins0 (+)0+

Therapeutic Strategies

The management options for patients with liver malignancies include LRx, LTx with or without embolization for bridging, chemotherapy, radiotherapy, hormone therapy, thermoablation, percutaneous ethanol injection, and even follow-up without any therapy.39 There was no generally accepted strategy for the treatment of HEH because of its rarity, heterogeneous status, and variable clinical outcome.37 In the published series, treatment methods were documented clearly in 286 patients. The most common management was LTx in 128 patients (44.8%), followed by no treatment in 71 patients (24.8%), chemotherapy or radiotherapy in 60 patients (21%), and LRx in 27 patients (9.4%) (Table 7).

Table 7. Different Treatment Modalities in 286 Patients with Adequately Documented Treatment Methods*
Outcome (n = 286 patients)No. of patients%
  • *

    Final outcome (alive or dead) was reported for 253 patients who received different modalities of treatment.

Liver transplantation (n = 128 patients; 44.8%)
 Alive7861
 Dead2318
 Unknown2721
Liver resection (n = 27 patients; 9.4%)
 Alive2178
 Dead14
 Unknown518
Chemotherapy and/or radiotherapy (n = 60 patients; 21%)
 Alive3558
 Dead2542
 Unknown00
None (n = 71 patients; 24.8%)
 Alive2840
 Dead4259
 Unknown11

Liver resection

In the published series, 9.4% of patients underwent LRx (Table 7). Theoretically, LRx is the first choice for curative treatment of HEH; however, in the majority of patients, an oncologic resection is impossible because of the multicentricity of the lesions1 or anatomic difficulties. Palliative resection is not advocated as a treatment method, because these tumors tend to behave aggressively after LRx.40, 41 Although clinical experience with tumor resection is satisfactory,42 some authors hesitate to perform LRx for patients with apparently resectable disease.43 The experience with local resection according to a report by Ben-Haim et al. was disappointing. Based on their experience, a possible explanation for the aggressive tumor behavior after resection may be tumor cell reactivity to the hepatotrophic growth factors that promote hepatic regeneration. The relative richness of specific antigens within tumor cells may support this theory.43 In contrast, extrahepatic spread at the time of LRx does not correlate with survival and has not been considered a contraindication to surgery.1, 31, 44 The number of reported patients who underwent LRx was not high; however, when LRx was performed as an acceptable therapeutic modality, the results seemed to be satisfactory.42

Liver transplantation

LTx generally was the most common treatment modality (44.8%) (Table 7). LTx for hepatic malignancy remains under debate, because HCC and cholangiocarcinoma are associated with a high recurrence rate after LTx45 and because of an increased death rate on the waiting list for LTx due to organ shortage in the last decade. In 1990s, Pichlmayr et al. defined 3 groups of hepatic malignancies based on patient outcomes after LTx. HEH was situated among the favorable indications for LTx. Other members of this group of malignancies included fibrolamellar carcinoma, hepatoblastoma, multiple adenoma, Stage I/II HCC, incidentaloma, and liver metastases from endocrine carcinoma.46 In addition, improved clinical outcomes after LTx in the last decade have provided further support in favor of undergoing LTx as curative treatment for HEH.42 The life expectancy of patients with HEH potentially is good; thus, limited extrahepatic disease should not be considered an absolute contraindication to LTx.41, 43 It should be noted that some authors have advocated LTx in the presence of extrahepatic involvement based on the reports of a 5-year survival rate between 50% and 71% in patients with HEH who had extrahepatic manifestations and underwent LTx.36, 37, 40, 43, 45 Adjuvant therapy for most extrahepatic lesions was chemotherapy. Long-term disease-free survival after LTx has been reported in patients who had a disseminated disease at the time of diagnosis; conversely, some patients with disease confined to the liver developed rapid recurrence and metastases after LTx.31, 43, 44 Thus, it would appear counterintuitive to allocate a donated liver to patients with HEH who have extrahepatic involvement. Conversely, significant symptomatic improvement with relatively stable extrahepatic residual disease also was achieved with LTx.45

Finally, because of the limited number of patients with HEH who underwent LTx in the presence of extrahepatic involvement, it was not possible to calculate any statistically proven results on the survival of patients with or without extrahepatic involvement who received different forms of therapy. Based on the authors' opinion, this dilemma may be addressed in future prospective, multicentric trials. Because of the reported unpredictable prognosis of patients with HEH, it can be postulated that there may be undefined subtypes with potential for different progression or recurrence. Conversely, the poor survival rates after LTx reported for patients with other primary liver malignancies and the long-term survival observed without any treatment in patients with HEH have led to debates among authors regarding the decision to perform LTx.39 Living-donor LTx may be advocated as a specific solution in highly selected patients, such as those who have bilobar involvement without extrahepatic manifestation, because it preserves the donor pool and addresses the problem of organ shortage. To date, 3 patients have undergone living-donor LTx for HEH. The first patient was a woman age 36 years who received a hemiliver from her sister.47 One year posttransplantation, because of portal hypertension and splenomegaly, she underwent proximal splenorenal anastomosis and splenectomy. At 3 years posttransplantation, she was free of recurrence. The second patient was a woman age 29 years who was reported by Langrehr et al.37 After 13 months of follow-up, she had returned to her job and was without any evidence of tumor recurrence. The third patient was a woman age 32 years who was reported by our group.42 After 24 months of follow-up, she was well and without evidence of recurrence. In general, if there is the possibility to have a donor for a patient with HEH, then a good clinical outcome after LTx can be achieved, especially at high-volume transplantation centers.

Chemotherapy, radiotherapy, and other therapies

At least 1 chemotherapeutic (systemic or regional) and/or radiotherapeutic modality was received by 21% of patients (Table 7). It was reported that, with the administration of thalidomide, the progression of a diffuse metastatic HEH was hindered successfully.94 Transarterial chemoembolization (TACE) may be a valid temporal intervention in patients with HEH who have advanced hepatic lesions and are waiting for LTx.47 Intraarterial chemotherapy with emulsion of mitomycin and lipiodol or with a combination of 5-fluorouracil, mitomycin, and doxorubicin was employed in 1 study at the end of 1980s. In that study, 5 patients received the therapy, 4 patients were alive from 25 months to 80 months of follow-up, and the tumor size was reduced in 2 patients.23 Moreover, absorbable, spongy, gelatin particles were received by 1 patient, and systemic immunotherapy with interleukin 2 was received by another. Both patients were alive at the time of the respective reports. To date, no reports are available on the use of new embolization materials, such as microspheres.

Leonardou et al. used chemotherapy to treat a patient with HEH who had bone metastases, although their report provided no additional data on the type or effectiveness of the chemotherapy regimen that was used.49 In a case report, Banerjee et al. described a woman age 29 years who received chemotherapy and was alive after 5 years, although her hepatic and pulmonary nodules had increased in size.17 In another case, chemotherapy was received by a patient age 33 years who, at first, was misdiagnosed with differentiated cholangiocarcinoma. The chemotherapy regimen contained doxorubicin, 5-fluorouracil, and vincristine.50 The patient was symptom-free in the presence of the primary tumor 10 years after diagnosis. Doxorubicin was used for the treatment of another patient with HEH who had extrahepatic involvement of the spleen and peritoneum: After 3 therapeutic courses, a marked regression was noted in both the number and the size of the tumors in the liver and spleen.51 In another patient, a combination of epirubicin and dacarbazine was used for the treatment of HEH with metastasis to pleura and bones.52 That regimen was not successful in controlling the disseminated disease. Another report about a patient with HEH who received intraarterial pump infusion chemotherapy with 5-fluorouracil described a reduced tumor mass and symptomatic improvement.53 Interferon α-2b was used as an adjuvant chemotherapy regimen after LTx in the setting of symptomatic extrahepatic disease in a woman age 21 years and resulted in substantial regression of extrahepatic disease and improvement of symptoms.54 Although that patient died of graft rejection caused by interferon, the effect of interferon α-2b on the course of extrahepatic HEH was noticeable.

Isolated radiotherapy was received by 4 patients for the management of HEH,1, 33, 55 but the reports did not mention any details of the doses. Although 3 patients were alive at the time of the reports, it was difficult to determine the effectiveness of this management modality. Most radiotherapies were applied in combination with chemotherapy; thereby reaching a conclusion about the effectiveness of radiotherapy is difficult. Kim et al. used radiotherapy for the management of massive pulmonary spread without any success.35 In some patients, the use of ligation of the hepatic artery as a palliative therapy has been reported without significant success.12 The experience with systemic or locoregional chemotherapy, TACE, and radiotherapy is limited and variable. Generally, these treatments are of limited value, especially as the first-line therapy.12, 41, 47, 56 Therefore, the significance of chemotherapy and/or radiotherapy is difficult to assess, mainly because of the lack of uniform treatment modalities and prospectively collected data.

No treatment

In the current study, approximately 25% of patients did not receive any treatment during the course of their disease (Table 7). At the time of report, >50% of those patients died. It is noteworthy that there are some reports of long-term survival in the presence of stable HEH without any treatments. For example, there is a report of 1 patient who was alive after 27 years.1 Clinical tumor regression also was reported in 1 patient after 10 years.1 It also is worth noting that 1 complete spontaneous regression recently was reported in a patient with HEH.32 Conversely, another patient died 2 weeks after diagnosis, demonstrating the unpredictable prognosis of HEH, which has aggressive potential in some instances. Until now, it is impossible to identify HEH reliably in patients with a nonaggressive tumors and to consider them for “no treatment” and a “wait-and-see” strategy.

Clinical Outcome

At the time of report, independent of their treatment modalities, 137 patients (45.7%) had tumor involvement, and 163 patients (54.3%) were free of tumor. The most common sites of involvement were liver (27.7%), lung (17%), peritoneum (9%), abdominal lymph nodes (6%), bone (5.7%), and spleen (4%) (Table 8). The other less common sites, in decreasing order, included pleura, mediastinum, mediastinal lymph nodes, heart, diaphragm, pericardium, retroperitoneum, abdominal anterior wall, kidney, brain, pancreas, pelvis, uterus, breast, thyroid gland, stomach, gallbladder, cervical lymph nodes, and ovary. Eleven patients (3.7%) had involvement in nonspecified sites. Because of the diversity of the reported patients in the published articles, it was very difficult to calculate an overall survival rate for HEH because of the different therapeutic methods. Yokoyama et al. reported 1-year, 3-year, and 5-year survival rates of 88%, 73%, and 48%, respectively, in 8 patients who underwent LTx.57 Seven of 21 patients in Penn's series developed recurrences, and the 2-year and 5-year posttransplantation survival rates were 82% and 43%, respectively. Most recurrences occurred beyond 2 years after transplantation.40 Pichlmayr et al. reported that the survival rate of patients with primary hepatic malignancies who had a favorable outcome, including HEH, hepatoblastoma, and cystadenocarcinoma, was approximately 55%.46 Madariaga et al., in a survey of 16 patients after LTx, reported 1-year, 3-year, and 5-year survival rates of 100%, 87.5%, and 71.3%, respectively. In that series, the 1-year, 3-year, and 5-year disease-free survival rates were 81.3%, 68.8%, and 60.2%, respectively.45 In the analysis by Lauffer et al. of 100 patients with documented HEH, the overall 5-year survival rate was 55.5% for all patients whether or not they received treatment.12 Recurrence rate was 27% in the series by Ben-Haim et al. that comprised of 11 patients who underwent different treatment methods.43 The survival rate after LTx for patients with HEH who had Stage IVA disease was more favorable compared with patients who had HCC at the same stage.45 Normally, there are 3 main causes for tumor recurrence and treatment failure after LTx that must be taken into account to further improve the clinical outcome: error in the pretransplantation evaluation, enhanced tumor growth under immunosuppressive therapy, and lack of effective anticancer therapy after surgery.57 In recent years, promising preliminary results were published from patients with liver malignancies who underwent LTx and received sirolimus for immunosuppression.48, 58

Table 8. Tumor Involvement in Patients with Hepatic Epithelioid Hemangioendothelioma (n = 137 of 300 Patients with Accessible Information) at the Time of Last Follow-Up*
Tumor involvement at the time of reportNo. of patients%
  • *

    Patients may have had > 1 involved site at the time of the report.

Without involvement16354.3
Liver8327.7
Lung, pleura5719
Peritoneum, omentum, mesentery279
Abdominal lymph nodes, retroperitoneum206.7
Bone175.7
Spleen124
Mediastinum, mediastinal lymph node103.3
Heart, pericardium72.3
Diaphragm31
Others165.3
Unknown113.7

In the current analysis, the survival data were available for 253 patients (Table 7). Among 101 patients who underwent LTx and had follow-up data available, 77% were alive at a mean follow-up of 45 months, whereas 23% of patients who had a mean follow-up of 41 months had died at the time they were reported. After LRx, the survival rate was 95% for all patients, with a mean observation time of 38 months in the patients who remained and with a mean survival of 15 months in the patients who died. The overall percentage of patients who remained alive, whether they received any kind of treatment or no treatment, was 83.4%, 55.8%, and 41.1% after 1 year, 3 years, and 5 years, respectively (Fig. 3). The surgical therapies, LTx and LRx, had the best survival rates with 5-year survival rates of 54.5% and 75%, respectively. The survival rates decreased markedly to 30% and 4.5% for patients who received chemotherapy/radiotherapy and patients who went without treatment, respectively (Fig. 3). Although the results of LRx have been good, it should be noted that HEH in most patients is not resectable because of its nature, which tends to involve the liver in a diffuse manner. Among the patients who received chemotherapy or radiotherapy, 58% remained alive at a mean follow-up of 43 months, and 42% died with a mean follow-up of 26 months. Forty percent of the patients who did not receive any kind of treatment remained alive after a mean follow-up of 32 months; however, 60% of patients died after mean of 8 months. It is noteworthy that a reduction in tumor size and spontaneous regression of the lesions also were reported in some patients who received no treatment. The following reasons may explain this phenomenon: 1) as hepatic parenchyma is infiltrated and destroyed by tumor nodules, progressive fibrosis occurs, resulting in cutting off the circulation of the neoplastic cells; 2) the tumor growth in the portal and hepatic venous systems further deprives the neoplastic cells of oxygen and nutrients1; and 3) the patient's immune system may limit or suppress the growth of the tumor. Tumor necrosis reportedly was associated with a poor outcome, although without statistical significance; whereas typical indicators of biologic aggression, such as nuclear atypia, capsule penetration, and the number of mitoses, reportedly were unrelated to clinical outcome.1 Although the tumor can spread to other organs, neoplastic spread does not appear to influence prognosis, as demonstrated previously.20 In this regard, the unpredictable natural course and prognosis of HEH make it difficult to determine a correlation between morphologic grading or clinical staging and outcome.12, 43

Figure 3.

This bar chart illustrates the 1-year, 3-year, and 5-year overall survival of patients who remained alive after different therapeutic modalities. LTx indicates liver transplantation; LRx, liver resection; Chemo/Radio, chemotherapy and/or radiotherapy.

Based on our analysis and available data, we suggest an algorithmic approach for the treatment of patients with HEH (Fig. 4). After histopathologic confirmation, the mode of hepatic involvement and the presence or absence of extrahepatic involvement are the main factors in the decision on a treatment modality. In resectable cases with no extrahepatic involvement, patients may undergo LRx as the first choice of treatment. The therapeutic strategy in the presence of extrahepatic involvement is especially controversial; and, from the available data, the best choice cannot be defined precisely. In the presence of extrahepatic involvement, independent of whether the patient undergoes LRx, adjuvant chemotherapy may be considered. In patients who have massive involvement of the liver, a total hepatectomy with LTx is the best therapeutic choice. Extrahepatic involvement does not exclude LTx. Although the application of chemotherapy in this situation is questionable, it may control the growth of extrahepatic tumor. It is noteworthy that the clinical course of HEH is variable, ranging from a favorable disease with prolonged survival, even without therapy, to a rapidly progressive disease with a grave outcome.

Figure 4.

This is a suggested schematic tree of therapeutic strategies for patients with hepatic epithelioid hemangioendothelioma (HEH). +, With; −, without; LRx, liver resection; Chemo., chemotherapy; TACE, transarterial chemoembolization; Radio., radiotherapy; LTx, liver transplantation.

In conclusion, the decision on a treatment strategy for HEH has to be tailored to each patient, and the individual rate of progression, severity of signs and symptoms, and response to other treatment modalities may be important determinants for decision making. Because of the lack of randomized clinical trials, the definite role of the treatment modalities described above cannot be determined to date. Conversely, because HEH is a rare disease, performing prospective randomized clinical trials may not be possible. Designing a worldwide data base that contains all data about patients with HEH independent to their therapy is highly recommended. With such a data base, the natural course of the disease and the roles of different treatment modalities may be defined better.

Acknowledgements

We thank Ms. Weiler, Director of the Library of Department of Surgery, University of Heidelberg, for her invaluable efforts in finding the articles.

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