Journal of Hepatology
Volume 47, Issue 4 , Pages 466-475, October 2007

Vascular and rare liver tumors: A good indication for liver transplantation?☆

  • Jan P. Lerut

      Affiliations

    • Abdominal Transplant Unit, Department of Abdominal and Transplantation Surgery, University Hospitals St. Luc, Brussels, Belgium
    • ,
  • Markus Weber

      Affiliations

    • Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery, University Hospital of Zürich, Rämistr. 100, 8091 Zürich, Switzerland
    • ,
  • Giuseppe Orlando

      Affiliations

    • Abdominal Transplant Unit, Department of Abdominal and Transplantation Surgery, University Hospitals St. Luc, Brussels, Belgium
    • ,
  • Philipp Dutkowski

      Affiliations

    • Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery, University Hospital of Zürich, Rämistr. 100, 8091 Zürich, Switzerland
    • Corresponding Author InformationCorresponding author.

published online 28 July 2007.

Article Outline

Abbreviations: ELTR, European Liver Transplant Registry, KMS, Kasabach-Merritt syndrome, (re-)OLT, orthotopic liver (re-)transplantation, TACE, transarterial chemoembolisation

 

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1. Introduction 

Despite the success of liver transplantation for many indications, its use for the treatment of primary and metastatic liver malignancies continues to be controversial. Non-epithelial hepatic tumors form a continuum starting with the completely benign haemangioma to the very aggressive haemangiosarcoma. Due to the often difficult differential diagnosis, the scarcity of malignant vascular lesions and scattered transplant experience worldwide, the value of orthotopic liver transplantation (OLT) in the treatment of these vascular diseases still remains questionable. Although even more controversial, OLT has been performed even for other rare malignant liver tumors like schwannoma, lymphoma or non-neuroendocrine metastasis. On the other hand, OLT can be an important therapeutic option for certain benign liver diseases such as echinococcus alveolaris, polycystic liver disease or adenoma.

This article is based on a review of the recent literature and the experience gathered by the European Liver Transplant Registry (ELTR) with the aim to summarize the current evidence for OLT for the treatment of vascular and other rare liver tumors.

During the period May 1968–December 2005, 12% (7360) of all European orthotopic liver transplantations (OLT) (n=60,011) were performed for hepatobiliary cancer, 125 (0.21%) for malignant vascular diseases; 20 of them for angiosarcoma, 7 for symptomatic giant haemangioma. In 300 (0.5%) cases OLT was performed for other primary liver malignancies and in 83 cases (0.1%) for non-neuroendocrine liver metastasis. Other rare indications for OLT were polycystic liver disease in 427 cases (0.7%), alveolar and cystic echinococcosis in 41 cases (0.07%), hepatic adenomas in 17 cases (0.05%).

Published data concerning these topics are limited and are based mostly on case series.

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2. Hepatic giant (cavernous) haemangioma 

Cavernous haemangioma is the commonest soft tissue tumor of the liver, the incidence ranging from 0.4% to 20% in autopsy series. Most haemangiomas are small (less than 4cm), solitary (90%), asymptomatic and diagnosed in adults on incidental medical check-up. The vast majority of haemangiomas remain stable in size [1]. Tumors greater than 4cm in diameter are called giant haemangiomas.

Complications of haemangioma are rather uncommon; they can include spontaneous bleeding and/or rupture, development of febrile syndrome and Kasabach-Merritt syndrome (KMS) [1], [2]. The latter syndrome is characterized by a localised clotting and fibrinolysis within the haemangioma associated with low platelet count and disseminated intravascular coagulopathy. In some patients giant haemangioma may cause invalidation due to the continuous slowly growing tumor.

MRI with vascular reconstruction is the best non-invasive diagnostic study; spiral CT remains a very valuable alternative.

The therapeutic algorithm for the management of giant haemangiomas is still not well standardised. Therapeutic modalities include medical treatment (using especially steroids), radiation therapy, arterial embolisation and/or ligation and finally different options of liver surgery [1], [2].

In the non-European transplant literature, seven OLT for giant haemangioma have been reported; six of them presented with KMS. One patient died of intracranial bleeding due to coagulopathy shortly after OLT; one patient had a successful early re-transplantation because of graft non-function.

Seven patients also have been reported to ELTR; five cases were already published in English literature. One patient was transplanted because of a ruptured giant haemangioma; three had invalidating symptoms and three presented with KMS. The patient with the ruptured haemangioma died of multiorgan failure after a two-stage OLT procedure. Two patients died late after OLT, one due to HIV infection and one due to an unspecified infection.

Two successful OLT have been reported for hepatic haemangiomatosis [3].

These data confirm that OLT is exceptionally indicated for giant haemangiomas and is usually performed in the setting of KMS. It is worthwhile to note that two cases have been published where the giant haemangioma (10cm) was resected on the back table with auto-transplantation [4].

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3. Hepatic epithelioid haemangioendothelioma 

Hepatic epithelioid haemangioendothelioma is a rare (<1/pmp), low grade malignancy which has a behaviour which is intermediate between haemangioma and haemangiosarcoma [5]. This vascular tumor was first recognized in soft tissues and later in the head and neck region, bones and in many other organs such as lungs. Hepatic epithelioid haemangioendothelioma is more frequent in adult women; the tumor has been exceptionally reported in children younger than 15 years old. No definitive etiological factor has been clearly identified [5].

This tumor originates from the endothelial cells which explains the positive staining for factor VIII-related antigen and the endothelial markers CD31 and 34. Macroscopically, hepatic epithelioid haemangioendothelioma appears as multifocal fibrous masses (Fig. 1). Microscopically, it is characterized by pleiomorphic, medium and large size cells, that are epithelioid in appearance and that spread within sinusoids and small veins. In contrast to haemangiosarcoma, the hepatic acinar landmarks are preserved [6], [7], [8].

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  • Fig. 1. 

    (a) Intraoperative view of 7.6kg heavy HEHE responsible for IVC-syndrome and supine dyspnoea. (b) Characteristic macroscopy of the HEHE hepatectomy specimen showing multiple fibrous masses with zoning phenomenon.

The clinical manifestation of hepatic epithelioid haemangioendothelioma is unspecific, varying from an asymptomatic state to hepatic failure. The malignant potential often remains unclear in the individual patient. The most frequent symptoms are unspecific right upper quadrant or epigastric discomfort or pain (60–70%), weight loss (20%), impaired general condition (20%) and jaundice (10%). About 20% of patients are asymptomatic and 10% present with pulmonary symptoms. Cholestasis and cytolytic activity are frequently present (60% and 40%, respectively), serum tumor markers however are often normal; KMS has been reported exceptionally. Hepatosplenomegaly (50%) is the most frequent clinical sign, portal hypertension may be caused by tumor compression or venous infiltration [6], [7], [8], [9] (Fig. 1).

Radiological investigation identifies two different patterns of hepatic epithelioid haemangioendothelioma: the early peripheral and nodular, usually bilobar, type (‘peripheral pattern’) and the later confluent type (‘diffuse pattern’) with eventual invasion of the greater vessels (Fig. 2). Focal classifications are present in 20% of tumors. Angiography reveals only moderate vascularisation with displacement of marginal vessels. Scintigraphic and FDG-PET imaging may have an important role in the staging of the disease, especially in view of later OLT [10]. Complete assessment of these patients is mandatory to exclude other, especially thoracic, disease localisation(s). The definitive diagnosis can only be made by associating radiological and clinical features such as the occurrence in a young adult, the contrast between numerous intrahepatic (calcified) tumors and the good condition of the patient and the longstanding clinical history. The diagnosis can only be confirmed by pathological examination of appropriate biopsy material.

The treatment algorithm of hepatic epithelioid haemangioendothelioma is far from standardised. The literature review, including 12 small (⩾5 pts) series and three reviews, lacks detailed data analysis and especially (long-term) follow-up. The published experience does not allow to compare results of untreated and of surgically and medically treated patients. The place of OLT is questioned in view of the documented spontaneous, long-term survivals, the high incidence of extrahepatic disease (up to 45%), the lack of predictive clinical or histological criteria and finally the high incidence (up to 33%) of (sometimes even very late) recurrent allograft disease [9].

The largest institutional series from Pittsburgh (16 patients) showed that OLT offers 5-year patient and disease free survival rates of 71 and 60%, respectively [11]. The Mehrabi review indicates that the treatment of choice of hepatic epithelioid haemangioendothelioma is total hepatic resection [6]. In this review, the 5-year survival rates of OLT, partial liver resection (only reported in a few patients!), local or systemic chemo- and radiotherapy and no treatment were 55%; 75%; 30% and 0%, respectively (Table 1). Partial resection is not a good treatment because hepatic epithelioid haemangioendothelioma is nearly always multinodular and bilobar. The assessment of non-surgical treatments such as radiotherapy, local tumor destruction, hormone treatment, systemic or locoregional radiochemotherapy, transarterial embolisation and chemoembolisation (TACE) is even more difficult because of the lack of uniform treatment modalities and of long-term follow-up [6].

Table 1. Liver transplantation for vascular and rare liver tumors
DiseaseAuthorsYearNumber of patientsDeathAlive5-year survivalTumor recurrenceMedian survival
Hepatic sarcoma
AngiosarcomaHusted et al. [20]200666002 months5.7
Maluf et al. [18]20057NRNRNRNR8.7 months
Penn [25]199114NRNR15% (2 year)NRNR
UndifferentiatedForbes et al. [46]1987220NRNRNR
CarcinosarcomaGarcez-Silva et al. [47]2006110NR3 monthsNR
Epitheliod hemangioendotheliomaMehrabi et al. [6]2006128237855%aNRNR
SchwannomaPenn [25]199111003 monthsNR
Hepatic lymphomaCameron et al. [29]2005321NRNRNR
Thompson et al. [45]2001431NRNRNR
Non-neuroendocrine hepatic metastasis
ColorectalHonore et al. [30]2003101 (10 yearsa)NRNRNR
Song XM [31]2005110NR5 monthsNR
GastricSong XM [31]2005211NRNRNR
BreastPenn [25]1991330NR12 monthsNR
GISTSerralta et al. [33]2004303NRNRNR
Cameron et al. [32]2005202NRNRNR
GIST or sarcomaHusted et al. [20]2006131038%11.7 months10.8
Hepatic benign tumors
Echinococcus granulosus cystsChomicz et al. [40]2003202NRNRNR
Ehinococcus alveolaris cystsChomicz et al. [40]2003202NRNRNR
Xia et al. [41]2005523NRNRNR
Bresson-Hadni [44]1999211110NRNRNR
Bresson-Hadni [42]200347143358%aNRNR
Polycystic liver disease
AdenomaLerut et al. [43]20058515NRNRNRNR
Yoshidome et al. [26]199960NRNRNRNR
Chiche et al. [27]200020NRNRNRNR

NR, not reported.

aTumor free.

The recent ELITA-ELTR approved study (accepted for publication in Annals of Surgery, 2007) conducted in 59 European patients, having a follow-up from OLT of 83±55 months, has validated the place of OLT in the treatment of this disease. Five and 10 year post-transplant survival rates are 83% and 74% and 5 and 10 years recurrence free survival rates are 82% and 64%. This study confirms that pre-OLT treatment (present in 30% of patients), invasion of lymph node (present in 33% of patients) and (limited) extrahepatic disease (present in 17% of patients) are no formal contra-indications to OLT. Micro- and macrovascular invasion (present in 40% and 10% of pts) however significantly influences outcome after OLT. Pathology of the hepatectomy showed bilobar disease in 96% of cases.

Recurrent disease should be treated aggressively as prolonged, sometimes even disease free, survival can be obtained (ELITA-ELTR study). The role of re-OLT in the treatment of recurrent allograft disease is still unclear [8].

The high incidence of extrahepatic disease localisation and of hepatic epithelioid haemangioendothelioma recurrence in- and outside the allograft should lead to the combined use of OLT and anti-angiogenic therapies using e.g. anti-V-EGF-antibodies and e.g. rapamycin. Mitotic index and cellular pleiomorphism are major histological prognostic criteria reflecting more aggressive tumor behaviour. Better study of the biological behaviour of the tumor, based on molecular and genetic markers, will be of help to improve outcome, to monitor the efficacy of emerging neo- and adjuvant treatments and to recognize the aggressive subtypes of hepatic epithelioid haemangioendothelioma [6], [12], [13], [14].

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4. Hepatic infantile haemangioendothelioma 

Hepatic infantile haemangioendothelioma, the most common tumor of the liver in infancy (<3 years) group, is nearly always diagnosed during the first six months of life. The tumor is more frequent in females and presents with (a)symptomatic hepatosplenomegaly, failure to thrive, congestive cardiac failure (15%) due to intratumoral arteriovenous shunting, and cutaneous haemangiomas (20–40%). Hepatic infantile haemangioendothelioma appears to be a histologically benign tumor, which may however have a poor outcome because of its complications such as heart failure [6], [15]. Histology identifies two types of hepatic infantile haemangioendothelioma; the more pleiomorphic character of type II does not seem to be a poor prognostic factor. The differentiation between hepatic epithelioid haemangioendothelioma and hepatic infantile haemangioendothelioma is important because the latter does not metastasize. Several lesions, present simultaneously in different organs such as spleen, lungs and bone, should probably be seen as separate lesions. Hepatic epithelioid haemangioendothelioma can be differentiated from hepatic infantile haemangioendothelioma as both have different, age-related, clinical and pathological features. The natural history of hepatic infantile haemangioendothelioma is variable but up to two-thirds of symptomatic patients die of tumor complications. Treatment modalities of hepatic infantile haemangioendothelioma vary from medical anti-angiogenic therapies (using or combining high dose steroids, interferon, chemotherapy or radiotherapy), over interventional radiological to surgical therapies [15], [16], [17]. Partial hepatectomy is indicated if lesions are confined to one liver lobe; diffuse lesions can only be treated by total hepatectomy and OLT. Recently the Boston group presented a clearly defined algorithm for the treatment of this paediatric condition [15]. Diffuse hepatic infantile haemangioendothelioma, resistant to steroid therapy, should be treated using OLT.

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5. Hepatic haemangiosarcoma 

Hepatic haemangiosarcoma is the most common primary sarcoma in the liver and accounts for up to 2% of all primary liver tumors. Peak age incidence is in the sixth and seventh decades of life with a male to female ratio of 3/1. Hepatic haemangiosarcoma has been rarely reported in children and is regarded as a distinct entity [6], [18].

Hepatic haemangiosarcoma has received much attention during the recent decade because of its frequent association with several environmental carcinogens such as thorotrast, vinyl chloride, monomer, radium, pesticides, external radiation, cyclophosphamid, arsenical compounds, use of androgenic/anabolic steroids and iron (haemochromatosis) [6].

A clear etiological cause of hepatic haemangiosarcoma is however frequently absent. The diagnosis, especially of diffuse hepatic haemangiosarcoma, can be extremely difficult. Liver biopsy has been reported as treacherous and non-diagnostic [19]. The most characteristic histological pattern is a scaffold like or tectorial growth of malignant endothelial cells on the surface of liver cell plates. Sinusoidal growth is associated with formation of larger vascular channels and cavernous space and papillary projections into their lumen.

Macroscopically, the hepatic haemangiosarcoma appears as an ill-defined spongic haemorrhagic nodule that involves the whole liver (Fig. 3b). Hepatic haemangiosarcoma can present four types of growth patterns: multiple nodules, large dominant mass, mixed patterns of multiple nodules and dominant mass and more rarely diffusely infiltrating macronodular tumor.

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  • Fig. 3. 

    (a) Characteristic macroscopy of the HAS hepatectomy specimen showing a diffuse spongy tumoral mass. (b) The corresponding CT-scan of HAS showing an infiltrating tumor mass.

At the moment of diagnosis, extrahepatic metastases are present in 20–40% of patients; the most common sites of metastases are lung, spleen, bone and adrenal.

Although with MRI the diagnosis of hepatic haemangiosarcoma is nowadays easier, the diagnosis still remains difficult. Histological diagnosis on adequate tissue is therefore of utmost importance.

In its early stages hepatic haemangiosarcoma may present with signs of portal hypertension, later on hepatosplenomegaly, pain, jaundice, ascites, peripheral oedema; acute abdomen due to tumor rupture and thrombocytopenia may follow.

Twenty hepatic haemangiosarcoma patients have been reported to the ELTR. Except for one, patients were symptomatic. Weakness and fatigue, upper abdominal pain and discomfort, anorexia and nausea were, respectively, present in 75%, 60% and 50% of the patients. Hepatomegaly was present in 80%, weight loss in 60%, jaundice and ascites in 45% of patients. One out of 4 patients presented with signs of portal hypertension and 10% of patients presented with liver failure. At the moment of OLT, 15% of patients presented with metastases.

The difficulty to diagnose hepatic haemangiosarcoma was underlined by the fact that pre-OLT diagnosis of hepatic haemangiosarcoma was only made in 30% of cases. The pathologic specimen showed diffuse bilobar involvement in all cases.

All patients died after a median of 7 months due to tumor recurrence. A patient in which an incidental hepatic haemangiosarcoma of 1cm was diagnosed in a cirrhotic liver also died 6 months post-OLT. Similar catastrophic results were recently reported by the Cincinnati transplant tumor registry in 6 patients [20] (Table 1).

The European and American experiences confirm that hepatic haemangiosarcoma is the (only remaining!) absolute contra-indication to OLT.

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6. Haemangiopericytoma 

Haemangiopericytoma is an uncommon vascular tumor comprising less than 2% of soft tissue sarcomas. The tumor arises from the pericytes of Zimmermann, the small oval cells that surround the capillaries. It is usually seen in adults of both sexes, as a painless mass. Lower extremities, abdominal cavity and retroperitoneal space are the most commonly affected sides; liver haemangiopericytoma is rare. These tumors can present as solitary but also as multiple lesions. Malignant haemangiopericytoma comprises about half of all described haemangiopericytoma. Specific features that qualify haemangiopericytoma as malignant lesions are tumor size (>20cm), more than four mitosis per 10 haemangiopericytoma, pleiomorphic cells with chromatin pattern and presence of central tumor necrosis or intratumoral haemorrhage.

Haemangiopericytoma is a hypervascular tumor. The tumor cells are mostly spindle-shape. Histological and especially immunohistochemistry usually allows for differentiation from other sarcomas [21], [22], [23].

Paraneoplastic syndromes may be seen with haemangiopericytoma either at presentation or at the moment of development of metastases. The hypoglycemia, related to the production of insulin like growth factors, is a characteristic feature in the later phase of tumor development. Radical excision is the treatment of choice for the primary as well as the metastatic haemangiopericytoma because chemotherapy and radiotherapy have a very unpredictable effect on tumor growth. Even after complete resection, two-thirds of patients experience local or distant recurrences. The detection of these recurrences is difficult because of the diversity of the recurrent tumor size and because of the lack of specific tumor markers. PET-scan may be a valid diagnostic procedure in the diagnosis as well as in the follow-up of these patients if the initial lesions showed tracer uptake.

Two patients with primary and two with metastatic haemangiopericytoma were reported to the ELTR. The two primary tumors were transplanted because of invalidating tumor growth; both patients died at 38 and 47 months post-OLT due to recurrent disease. Two patients were transplanted because of a paraneoplastic syndrome of non-insulinoma hypoglycemia. One patient died 34 months post-OLT due to pulmonary recurrence diagnosed 1 year earlier. The second patient still survives disease free 12 years after OLT and 23 years after resection of the original adrenal tumor. After OLT, he had several abdominal, thoracic and orthopedic surgeries in order to successfully treat different metastases [24].

After complete excision, 5 year disease free survival is about 50%. Long-term follow-up remains necessary as 10% of tumors recur after 5 years. Repetitive surgery may be useful in case of appearance of paraneoplastic syndromes in particular of invalidating hypoglycemia [23].

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7. Hepatic schwannoma 

Malignant schwannoma represents 10% of all soft tissue sarcoma. The incidence in the general population is about 1 per 10,000. Schwannomas are often associated with von Recklinghausen’s disease. On CT imaging schwannomas appear as a well-circumscribed hypodense mass with no enhancement of contrast. Very few reports are documented with schwannoma of the liver. One patient underwent OLT for malign hepatic schwannoma but prognosis was poor. The patient died 3.5 months after transplantation due to tumor recurrence [25].

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8. Hepatic adenoma 

Adenomas of the liver are benign neoplasms associated with oral contraceptive use in women, anabolic steroid use in men or occur in patients with glycogen storage disease. Multiple adenomas are described in about 21% of these patients. Malignant transformation is rare but has been reported. The risk of haemorrhagic complications is difficult to estimate.

Hepatic adenomas show increased contrast uptake in the arterial phase of CT or MRI-scans. MRI provides more information on the nature and the number of lesions. Two case series report on liver transplantation for hepatic adenomas in 6 patients [26] and 2 patients [27]. No mortality is reported.

The treatment for symptomatic or suspicious lesions remains resection. Liver transplantation is an ultimate option for multiple large hepatic adenomas or centrally located lesions, but should be performed only in the event of disease progression.

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9. Hepatic lymphoma 

Abdominal lymphomas represent less than 2% of abdominal malignancies. The most frequent locations are the stomach, the small and large bowels and the pancreas. Hepatic lymphoma is defined as primary when the disease is confined to the liver without extrahepatic nodal involvement or when the presentation is predominantly in the liver. Primary hepatic non-Hodgkin lymphomas can be divided into two groups: nodular or diffuse with respect to the nature of liver infiltration. They may be of either T- or B-cell origin. Hepatic lymphoma typically occurs during the fifth decade of life and has a male predominance.

Ultrasonography, computed tomography and magnetic resonance imaging cannot clearly differentiate lymphoma, only histological examination of liver biopsy will confirm diagnosis.

Overall median survival of patients with primary hepatic lymphoma has been estimated at 15 months under chemotherapy, although survival also has been reported up to 10 years [28]. A subset of patients with primary hepatic lymphoma present with fulminant liver failure. Seventeen cases were reported, four of them survived after chemotherapy [29]. In contrast to patients with fulminant hepatic failure, diagnosis is often elusive in patients with primary hepatic lymphoma and is made post-mortem in the majority of cases. In the situation of an unclear fulminant hepatic failure with no specific findings on liver biopsy OLT has been reported in three cases. Two of those patients died shortly after transplantation, one patient recovered uneventful ([29], Table 1).

These data show that primary hepatic lymphoma can be an extremely rare cause of fulminant hepatic failure. Patients with proven diagnosis of lymphoma should receive prompt treatment with chemotherapy. In those where diagnosis is impossible, OLT can be a lifesaving option.

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10. Non-neuroendocrine hepatic metastasis 

For most centers metastatic disease is considered as an absolute contra-indication for OLT except when the primary disease is a neuroendocrine tumor. In spite of that, OLT also has been performed for multiple non-neuroendocrine hepatic metastasis. One patient received OLT as rescue therapy for acute liver failure after liver resection of an isolated hepatic colon cancer metastasis [30]. This patient survived 10 years without tumor recurrence after liver transplantation. In three other cases radical resection after gastric or colorectal cancer was combined with OLT for multiple hepatic metastasis. The gastric cancer patient died of recurrence 5 months after operation. One rectal cancer patient died of hepatic failure 7 months after operation without recurrence [31]. The other rectal cancer patient recovered well ([31], Table 1).

Another series report about OLT in 13 patients with metastatic sarcoma [7], the most common site of origin being the gastrointestinal tract, followed by extremities. Of the patients with primary gastrointestinal sarcoma, 6 patients had a leiomyosarcoma of the stomach, 1 patient presented with a leiomyosarcoma of the pancreas and one patient with a leiomyosarcoma of the small intestine (GIST). The sarcoma of the extremities were either spindle cell sarcoma or a fibrosarcoma. All patients were free of extrahepatic disease at the time of transplantation. Twelve of 13 patients had tumor recurrence after a median time of 11.7 months. Median survival was 10.8 months (range 2–60 months). Ten of 13 patients (77%) died of recurrent and diffuse metastatic disease. The 1-, 3- and 5-year survivals were 62%, 23% and 8% ([20], Table 1).

Two other case series also report on results after OLT for metastatic GIST tumors [32], [33]. The primary tumors were located in the duodenum or stomach. After removal of the primary tumor patients presented with liver metastasis and were transplanted. All 5 patients are alive with a follow-up of 48, 69 months [19] and 60, 14, 19 months, respectively [33]. Three patients showed tumor recurrence which was located either in the lungs (n=1), the liver (n=1) or in the pancreas (n=1) [33]. Penn reported three cases in which OLT was performed for metastatic breast cancer [25] without extrahepatic tumor presence. All patients developed tumor recurrence and two patients died within 1 year. One patient survived for more than 4 years ([25], Table 1).

These case series show that OLT cannot be recommended in cases with metastatic colorectal, breast or gastric cancer. It may provide in highly selected situations some survival opportunity. For other non-neuroendocrine metastatic diseases no reports are currently available concerning OLT.

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11. Other rare indications 

Here we discuss the potential indications for OLT and results for patients with nodular regenerative hyperplasia, Echinococcus granulosus or alveolaris and polycystic liver disease.

11.1. Nodular regenerative hyperplasia 

Nodular regenerative hyperplasia of the liver is a rare condition which most often presents with stigmata of portal hypertension and its sequelae [34]. Its prevalence is estimated between 0.70% and 2.6% in autopsy series. Nodular regenerative hyperplasia is the major cause of non-cirrhotic portal hypertension. Current theories favour a primary vasculopathy with alterations in blood flow as the causative agent. It is supposed that the presence of a portal venopathy (occlusion or terminal portal venules) with or without accompanying hepatic arterial disorders leads to diffuse microvascular transformation leading finally to nodular regenerative hyperplasia. When a critical proportion of portal venules are affected, portal hypertension ensues. Nodular regenerative hyperplasia is characterized by the formation of usually small (up to 1cm) non-fibrotic parenchymal nodules. This characteristic allows to distinguish it from micronodular cirrhosis. Haemodynamic investigation shows presinusoidal and sometimes sinusoidal portal hypertension in association with a patent portal vein.

Various (systemic) diseases are known to occur in association with nodular regenerative hyperplasia such as primary biliary cirrhosis Budd-Chiari syndrome, lympho- and myeloproliferative disorders, collagen-vascular diseases, congenital and acquired hepatic macrovascular abnormalities as well as exposure to toxins such as azathioprine and some chemotherapeutic agents. Familial cases of nodular regenerative hyperplasia of the liver occurring without underlying or associated systemic disease have been described [35]. These forms have a poor clinical course and are often associated with progressive renal failure.

Six patients with nodular regenerative hyperplasia have been reported to the ELTR. Four had a favorable outcome; two died at 20 and 42 months post-transplantation due to cardiac failure. Three patients had to be treated previously because of ruptured oesophageal varices; three presented with cholestatic cirrhosis, one of them was complicated with hepatopulmonary syndrome. One patient had a previous kidney transplantation. Four larger series and some case reports about successful OLT for this condition have been reported in the literature [36], [37], [38].

In relation to OLT, it should be noted that recurrent allograft nodular regenerative hyperplasia has been reported. In addition, nodular regenerative hyperplasia has been described as a complication of chronic immunosuppression using azathioprine, leading even to re-OLT. Furthermore, nodular regenerative hyperplasia has been described in the context of living donor liver transplantation using small-for-size grafts and in recipients transplanted for biliary tract disease complicated with severe non-cirrhotic portal hypertension [36], [37], [38], [39].

11.2. Echinococcus (E) granulosus or alveolaris cysts 

Echinococcus alveolaris is often compared with a slow-growing liver cancer with invasion of bile ducts and vessels. Severe complications include cholangitis, liver abscess, septic shock, portal hypertension, biliary cirrhosis or Budd-Chiari syndrome. Magnetic resonance imaging provides the best information regarding the location and the extent of intraabdominal hydatid disease. However, it is often difficult to differentiate malignant tumors from alveolar echinococcosis by imaging techniques. Even with new PCR techniques or parasitological examinations, the correct diagnosis of E. alveolaris may be confirmed only at operation by histopathology.

The criteria for OLT in a patient with E. alveolaris are the absence of extrahepatic disease combined with severe liver insufficiency not responding to medical therapy. The post-transplantation survival in five cases ranged between 0.8 and 39 months, two patients died on post-operative complications, while three patients were alive [41]. Forty-seven patients are reported from European centers concerning liver transplantation for E. alveolaris [42]. One patient died during hepatectomy, three patients after liver removal. The mean transfusion requirement was 10.6 units. Ten patients needed early re-operation after transplantation because of perihepatic clotting (n=4), hepatic artery thrombosis (n=2), hepatic artery folding (n=1), diaphragmatic rupture (n=1), primary non-function (n=2) [42]. Survival rates without recurrence were only 58% at 5 years, and 45% at 10 years ([42], Table 1). It is important to note that continuous treatment with albendazole is crucial.

The optimum procedure for E. granulosus within the liver depends on stage of the parasitosis and the patient’s general health status. If the hydatid cyst is totally removed, usually by resection, but in exceptional cases also by liver transplantation, the patient is cured and full recovery is reported [40].

Based on this, liver transplantation for E. granulosis and even E. alveolaris appears feasible and could be part of the therapeutic options but only if meticulous pre transplant evaluation of extrahepatic lesions has been performed and conventional surgery is not feasible and medical treatment fails.

11.3. Polycystic liver disease 

Unlike simple cysts, polycystic liver disease is inherited either autosomal recessively in childhood or autosomal dominantly in adulthood. Both forms are associated with polycystic renal disease and progressive renal failure. Liver failure is rare because liver function is well preserved in most cases. Thus, liver transplantation is an infrequent therapeutic option for polycystic liver disease. On the other hand, quality of life can be severely impaired by the huge hepatomegaly due to portal hypertension and compression of the v. cava. Diagnosis is readily confirmed by CT-scan.

Early morbidity and mortality of liver transplantation for polycystic liver disease are reported up to 36% and 17% [43], mainly because of septic multiorgan failure and bleeding. A summary of reports concerning liver transplantation shows a high mortality (<3 months) of 18% (15/85) [43] due to the difficult hepatectomy. However, OLT for a benign, non-life threatening liver disease can only be justified if morbidity and mortality are lower compared to conventional surgery and if long-term quality of life is clearly improved. Underlining this, a recent case series report OLT without complications and with minimal blood loss in 6 patients suffering from polycystic liver disease [43].

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12. Conclusions 

Due to their scarcity, indications of liver transplantation for vascular tumors or other rare tumors are many times either unknown or incorrect. The review of the literature and of European Liver Transplant Registry data has permitted to clarify this matter.

OLT is very exceptionally indicated in case of giant haemangioma; most indications relate to the presence of a clinically relevant Kasabach-Merritt syndrome. OLT is absolutely contra-indicated in case of haemangiosarcoma due to the very rapid and aggressive disease recurrence. Hepatic epithelioid haemangioendothelioma in contrast may represent an excellent indication for OLT allowing long-time (disease free) survival even in the presence of extrahepatic disease localisation at moment of transplantation. Haemangiopericytoma may in some exceptional cases benefit from OLT in terms of improved quality of life. Severe non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia can be cured by liver transplantation.

OLT is not indicated in case of hepatic schwannoma, lymphoma and non-endocrine hepatic metastasis. However, OLT appears as an option for certain benign hepatic tumors (echinococcus cysts, polycystic liver disease, adenoma) if conventional surgery is not feasible, if quality of life clearly improves post-transplantation and if the estimated perioperative risk is low.

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Acknowledgements 

The authors would like to express their thanks to Dr. Vincent Karam (from the Abdominal Transplant Unit, Department of Abdominal and Transplantation Surgery, University Hospitals St. Luc, Brussels) for his valuable contribution to this article, and the ELTR – European Liver Transplant Registry – for making their data available.

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References 

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☆ The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

PII: S0168-8278(07)00400-X

doi:10.1016/j.jhep.2007.07.005

Journal of Hepatology
Volume 47, Issue 4 , Pages 466-475, October 2007

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