Liver Transplantation for Primary or Metastatic Sarcoma to the Liver

Authors


*Corresponding author: J.F. Buell, joseph.buell@uc.edu

Abstract

Sarcoma is generally a rare disease in the US, with poor survival in patients with both primary angiosarcoma and metastatic disease from sarcoma and GIST. In order to determine if liver transplantation for sarcoma is a realistic option, we examined records of all patients in the US component of the Israel Penn International Transplant Tumor Registry were reviewed. Those patients with liver failure from primary or metastatic liver sarcoma were evaluated. Patient outcome analysis was then performed. Patient and tumor demographics were reviewed as well as patient survival after transplantation. 19 patients are identified having received liver transplantation after treatment for sarcoma of the liver, 6 patients with primary hepatic sarcoma and 13 patients with metastatic sarcoma of the liver. Recurrence was almost universal in 18 of 19 patients (95%) after a median interval of 6 months. Survival for the group as a whole was 47% for 1-year, 15% for 3-years and 5% for 5-years. Given the early recurrence of tumor and meager 1-year survival outcome, liver transplantation is a poor therapeutic choice for patients with either primary or metastatic liver sarcoma, including high-grade leiomyosarcoma (GIST) regardless of primary site or primary therapy.

Introduction

Liver transplantation has evolved from its infancy and has now become the gold standard therapeutic modality for the management of several conditions leading to end-stage liver disease (ESLD). Despite this success of liver transplantation, its use for the management of primary and metastatic liver malignancies continues to be controversial. Penn first reported on a large registry cohort that patient survival after liver transplantation for hepatic malignancy was a meager 18% at 5 years (1). This poor survival reflects the era in which it occurred. During the initial experience with malignancy, transplant surgeons reserved liver transplantation for often large and unresectable tumors. The poor long-term survival reflects this fatalistic approach.

During the last three decades, aside from dramatic changes in surgical technique, immunosuppression has also been revolutionized from combination therapy incorporating azathioprine-free and steroids to steroid-free liver transplantation with calcineurin minimization. The initial bleak results from liver transplantation for hepatocellular cancer led to introspection and eventual innovation. Mazzefero and his group reported what has come to be known as the Milan Criteria (2). These criteria stipulate that patients with a single tumor less than 5 cm or up to three tumors with the largest tumor less than 3 cm could be transplanted with an acceptable recurrence rate and survival. Transplantation while utilizing these criteria for hepatocellular cancer within the Milan Criteria achieve 4-year survival rates of 85% to 92%.

During this same 30-year interval, transplant surgeons have sought to treat atypical tumors including hemagioendotheliomas, carcinoid and sarcoma. Sarcomas are rare soft tissue tumors with a high propensity for local and distant recurrence. Less than 8000 new cases are diagnosed each year in the United States, accounting for approximately 1% or less of all adult malignancies (3). Unfortunately, high-grade sarcoma has a high propensity for metastatic spread, with the liver being a common site. In patients with sarcoma metastatic disease to the liver may be common, however, as a primary site sarcoma of the liver is exceedingly rare. In the circumstance of limited disease, treatment options vary from partial hepatectomy to systemic chemotherapy with or without radiotherapy. Despite multiple prospective randomized trials of adriamycin- and platinum-based therapy, few sarcoma subtypes respond dramatically to systemic or local chemotherapy (4,5). This has left partial hepatectomy as the mainstay for disease control.

In 1983, Mazur and Clark introduced the term “stromal tumor” in recognition of gut wall tumor lacking immunohistochemical or electron microscopic evidence of smooth muscle. Despite the name change, high-grade gastrointestinal stromal tumors (GISTs) exhibit a behavior akin to sarcoma. GIST is rarely invasive but nearly 50% are overtly metastatic at presentation, and prognostication deriving from tumor size and mitotic index (6,7).

In the event of isolated liver metastases from sarcoma with a diffuse bilobar pattern, liver transplantation has been advocated (8). To date, aside from several case reports no literature exists on the utility of liver transplantation in the management of primary or metastatic sarcoma of the liver (9). This study seeks to outline the efficacy and pitfalls of such an approach.

Materials and Methods

All patients in this retrospective study were identified in the domestic component of the Israel Penn International Transplant Tumor Registry (IPITTR).

The IPITTR is a voluntary reporting database collecting data of the incidence of cancer in solid organ transplant patients begun in 1968 as the Denver Transplant Tumor Registry. Penn began collecting data to analyze the relationship between immunosuppression and cancer in transplant recipients. When Penn moved to Cincinnati, the registry was renamed the Cincinnati Transplant Tumor Registry. After his death in 1999, the registry was again renamed in his honor, to the IPITTR. The Registry has data on over 7000 types of cancer that have developed in U.S. transplant patients. We evaluated all reported cases of sarcoma in U.S. transplant recipients reported to the Registry for the period of 1983 to 2005. Nineteen patients reported from 11 transplant centers received liver transplantation for primary or metastatic sarcoma of the liver.

Patient demographics, tumor characteristics, recurrence and survival rates were examined. Univariate data analysis was undertaken of patient demographics. Actuarial 1-year survival was calculated using the Kaplan-Meier method.

Results

The report is based on orthotopic liver transplantation for primary or metastatic sarcoma of the liver in 19 patients (Table 1). The decision to proceed to transplantation was made on an individual basis with all patients in this cohort proceeding to transplantation when their tumor was deemed unresectable (Figure 1).

Table 1.  Demographics of tumor and patients with sarcoma receiving liver transplantation
 Primary sarcomaMetastatic sarcoma and GISTAll sarcoma
n%n%n%
Gender
 Male233754947
 Female4666461053
Median age at transplant (years)53.3 38.6 46.3 
Histology
 Angiosarcoma6100216842
 Gastrointestinal leiomyosarcoma00861.5842
 Fibrosarcoma001815
 Spindle cell sarcoma001815
 Unspecified001815
Site of primary sarcoma
 Liver610000631.5
 Gastrointestinal tract00861842.5
 Extremities00323316
 Head and neck001815
 Heart001815
Recurrence of sarcoma610012921895
Median time to recurrence after transplant (months)2 11.7 6 
Therapy for recurrence
 Chemotherapy (adriamycin)350431737
 Radiotherapy11718211
 Surgical resection117754842.5
Median survival (months)5.7 10.8 9 
Figure 1.

Computed tomography of liver showing sarcoma involving the right lobe. This patient later received orthotopic liver transplantation.

Primary sarcoma

Liver transplantation was performed for primary sarcoma of the liver in 6 patients reported from three transplant centers (Table 1). Four patients were women and 2 patients were men. These patients were transplanted at a median age of 53.3 years (range 35–66.8 years). Histopathologic examination of these tumors revealed that all patients had primary hepatic angiosarcoma. All patients received cadaveric liver transplants while having no evidence of metastatic disease outside of the liver. No patient in this group received an extended criterion, cluster or multi-organ transplant.

Patients with primary hepatic sarcomas had recurrence of disease at a median interval of 2 months (range 2–10 months) after liver transplantation. All recurrent disease identified was isolated to the transplanted liver. There were numerous approaches to the treatment of recurrences. Three patients received systemic adriamycin-based systemic chemotherapy. One patient received radiotherapy and 1 patient received subsequent hepatic resection. One year disease-free survival for patients with primary sarcoma of the liver who received liver transplantation was investigated using Kaplan-Meier analysis (Figure 2A). Despite all interventions, the median survival for this group was 5.7 months (range 2.6–15.4 months) after transplantation. All patients died of recurrent disease with only 1 patient surviving to the 1-year interval (Figure 2B).

Figure 2.

Figure 2.

(A) Disease free survival for patients with primary hepatic sarcoma after liver transplantation. (B) Survival for patients with primary hepatic sarcoma after liver transplantation. Data are plotted in the form of Kaplan-Meier.

Figure 2.

Figure 2.

(A) Disease free survival for patients with primary hepatic sarcoma after liver transplantation. (B) Survival for patients with primary hepatic sarcoma after liver transplantation. Data are plotted in the form of Kaplan-Meier.

Metastatic sarcoma

Thirteen patients received liver transplantation for isolated metastatic sarcoma to the liver (Table 1). Six patients were women and 7 patients were men. These patients were transplanted at a median age 38.6 years (range 15.4–58.1 years).

Of the 13 patients with metastatic sarcoma, the most common site of origin was the gastrointestinal organs (8), followed by extremities (3), head and neck (1) and the heart (1). Of the patients with primary sarcoma located in the gastrointestinal tract, 6 patients had primary leiomysarcomas of the stomach (46%) with one each leiomyosarcoma of the pancreas and small intestine. The histologic characteristics of the extremity sarcoma were one each of spindle cell sarcoma, fibrosarcoma and unspecified histology. Angiosarcomas were found in the sarcoma originating in the head and neck region and the heart. All patients had prior control of their primary malignancies before consideration for liver transplantation, and all patients receiving cadaveric liver transplants were free of extrahepatic disease at the time of liver transplantation. No patient received an extended criterion, cluster or multi-organ transplant.

Twelve of the 13 patients (92%) had recurrence of their disease after a median time of 11.7 months (range 2–90 months). One patient (8%) with primary small intestinal sarcoma with hepatic metastases had no recurrence after liver transplantation. Four patients (31%) received adriamycin-based systemic chemotherapy as a salvage effort. Several patients had undergone extensive resectional therapy, including radical mastectomy (2), hemi-mandibulectomy (1), hepatic resection (2) and retroperitoneal resection (2). Another recipient received brachytherapy. Median survival for the group 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%. One-year disease-free survival for patients with primary sarcoma of the liver who received liver transplantation was investigated using Kaplan-Meier analysis (Figure 3A).

Figure 3.

Figure 3.

(A) Disease-free survival for patients with metastatic hepatic sarcoma after liver transplantation. (B) Survival for patients with metastatic hepatic sarcoma after liver transplantation. Data are plotted in the form of Kaplan-Meier.

Figure 3.

Figure 3.

(A) Disease-free survival for patients with metastatic hepatic sarcoma after liver transplantation. (B) Survival for patients with metastatic hepatic sarcoma after liver transplantation. Data are plotted in the form of Kaplan-Meier.

Three patients are currently alive after a mean of 38.7 ± 46.2 months (Figure 3B). Two are disease free while one has a spinal metastasis treated with localized radiation.

All 3 surviving patients are maintained on imatinib mesylate.

Tumor classification

As the molecular, biological and clinical characteristics of sarcoma have become increasingly understood over the last decade, the nomenclature has also evolved. What was previously described as leiomyosarcoma of the stomach in the past would today most likely be labeled gastrointestinal stromal tumor (GIST) after a review of histologic slides (10). All presumed GIST tumors in our study were reported to be of high mitotic activity, which currently predicts aggressive tumor behavior. As molecular and biological progress is made in the understanding of these tumor types, a universal classification system will become available.

Combined data

In summary, 19 patients received liver transplantation for either primary or metastatic sarcoma to the liver (Table 1). Ten patients were women and nine were men. Median age at transplantation was 46.3 years (range 15.4–66.8 years). Median wait time to transplantation from diagnosis was 6 months (range 0–102 months). Six patients had primary sarcoma of the liver and 13 patients had metastatic disease from predominantly gastrointestinal leiomyosarcoma. Five patients received adriamycin-based chemotherapy prior to transplantation with variable responses. All patients received cadaveric organs with no evidence of extrahepatic disease at the time of organ transplantation. Recurrence was almost universal in 18 of 19 patients (95%) after a median interval of 6 months (range 2–90 months). Typical sites of recurrence are demonstrated (Figure 4). Retroperitoneal and breast recurrence is common, but mandible recurrence is rare. Survival for the group as a whole was 47% for 1 year, 15% for 3 years and 5% for 5 years (Table 1).

Figure 4.

(A) Computed tomography of abdomen showing 1.7 × 1.3 soft tissue mass in the soft tissue of the right retroperitoneum, which was a recurrence of sarcoma after liver transplantation for primary sarcoma of the liver.(B).Computed tomography of chest showing asymmetry of the left breast soft tissue with skin thickening, which was a recurrence of sarcoma after liver transplantation for primary sarcoma of the liver.(C). Magnetic resonance image of head showing 2.6 × 2.2 × 1.0 cm expansile lytic lesion in body/ramus of left mandible with soft tissue extension; a rare mandibular recurrence of sarcoma after liver transplantation for primary sarcoma of the liver.

Discussion

Liver transplantation continues to evolve as a medical modality particularly in the treatment of malignancy. Better patient selection has equated to improved survival in the transplantation of hepatocellular and hemangioendotheliomas tumor patients (8,11). These successes, and the ability to perform living donor right lobe hepatectomy, have reinvigorated the efforts to treat hepatocellular cancer (outside the Milan criteria) and nonhepatocellular malignancies with liver transplantation. These nonhepatocellular tumors include hemangioendothelioma, carcinoid, sarcoma and even colorectal metastases. As underscored by the outcomes in this study it is fortunate that primary and metastatic sarcomas of the liver are exceedingly rare.

Despite combining primary hepatic sarcoma and metastatic sarcoma to the liver, including leiomyosarcoma of GIST, we have shown that these tumors all demonstrate poor outcomes. Our study identified an almost universal recurrence rate within the first 6 months after liver transplantation. As in resection of high-grade sarcomas in other locations, most recurrences will occur during the first 2 years after primary resection. In the liver transplant patient, this may be reflective of two key factors: (1) high-grade tumors with aggressive biologic behavior and (2) the effects of chronically suppressed immune system. All tumors in our study were identified as either high-grade primaries or metastases. As for the importance of an immunosuppressed state, sarcoma was the first tumor to demonstrate immunoresponsiveness to BCG, thus further clouding the issue (12). Malignancy in solid organ recipients has routinely shown a propensity for aggressive behavior (13). Transmission of metastatic cells with a transplanted organ can and has resulted in patient demise. Reactivation of melanoma, Kaposi's sarcoma and renal cell have been observed after organ transplantation (14). De novo malignancies, including nonmelanoma skin cancers, have been observed at considerably younger ages in the transplant population than the general population and behave more aggressively (15). Other solid organ malignancies including breast, colon, lung and pancreas have shown inferior survival compared to the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (16).

The clinical course of sarcoma survivors illustrates the tumor biology of high-grade sarcoma with multiple recurrences at short intervals. Aggressive surgical debulking and significant reduction in immunosuppression can result in increased patient survival despite repetitive tumor recurrences (17). This must be compared with the results of traditional hepatectomy and/or serial resection. The most extensive experience with hepatectomy for metastatic sarcoma to the liver was reported by the Memorial Sloan Kettering group (18). This study demonstrated 56 patients with a 1-, 3- and 5-year survival of 88%, 50% and 30% after hepatic resectional therapy. The majority of patients were resected for either GIST or other forms of leiomyosarcomas. This series did not report on resection for angiosarcoma. Forty-seven (84%) patients recurred with 31 (55%) dying of disease. The most common site of recurrence was the liver, being involved in recurrence patterns 56% of the time. Nine patients had multiple sites of recurrence. Six patients underwent repeat hepatic resection. Another 12 patients (32%) underwent resection for extrahepatic metastases. Analysis of this series identified occurrence of hepatic metastases greater than 2 years after primary resection as the only positive prognostic variable. The presence of extrahepatic disease and extent of hepatic resection demonstrated a trend toward statistical significance. These data confirm resection as a viable option for metastatic sarcoma to the liver with significantly better survival rates when compared to liver transplant recipients. Similar to resection therapy for liver sarcoma, transplant patients with longer intervals between recurrences appear to adopt a survival benefit.

When one compares the results obtained from liver transplantation for alcoholic liver disease (1-, 3- and 5-year patient survival of 77%, 69% and 61%) and hepatitis C (1-, 3- and 5-year patient survival of 79%, 79% and 66%), the resulting 1-, 3- and 5-year survival of 47%, 15% and 5% achieved after transplantation for primary or metastatic sarcoma are unconscionable. Currently, over 50 000 patients are awaiting liver transplantation in the United States. During an average year, over 17,000 suitable liver donors are transplanted. This disparity should underscore the ethical dilemma in the proper utilization of a scarce resource. Despite trivial successes, the authors of this article strongly discourage the use of liver transplantation for the management of primary or metastatic sarcoma to the liver.

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