1391
Management of Primary Liver Sarcomas
Jürgen Weitz, MD1
David S. Klimstra, MD2
Karina Cymes, MD2
William R. Jarnagin, MD1
Michael D’Angelica, MD1
Michael P. La Quaglia, MD1
Yuman Fong, MD1
Murray F. Brennan, MD1
Leslie H. Blumgart, MD1
Ronald P. DeMatteo, MD1*
BACKGROUND. Primary hepatic sarcoma is a rare entity. The objectives of the
study were to define treatment and long-term outcome and to identify prognostic
factors.
METHODS. Between January 1981 and December 2004, 30 patients with primary
sarcoma of the liver and 5 patients with primary carcinosarcoma of the liver
were treated. Patient demographics, tumor characteristics, treatment, and actuarial survival were analyzed.
RESULTS. Of the 30 patients with primary hepatic sarcoma (10 epithelioid
hemangioendothelioma, 5 embryonal sarcoma, 5 angiosarcoma, 3 solitary fibrous
tumor, and 7 other types), 11 underwent R0-resection and had a 5-year diseasespecific survival of 64%. Of these 11 patients, 4 had low-grade sarcoma and have
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
not developed tumor recurrence. In the group of 7 patients with high-grade sar-
2
within 11 months, whereas the 5 patients with embryonal sarcoma had a 5-year
1
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
comas who underwent R0-resection, both patients with angiosarcoma died
disease-free and disease-specific survival of 80%. Six of the 10 patients with an
epithelioid hemangioendothelioma were managed without surgery, as they had
diffuse, slowly progressing, or stable lesions; these patients had a 5-year diseasespecific survival of 67%. Of the remaining 13 patients in whom R0-resection was
not performed, there were no 3-year survivors. The prognosis for patients with
primary carcinosarcoma of the liver was poor, with all but 1 patient dying within
a year and no 3-year survivors.
CONCLUSIONS. The outcome of patients with primary hepatic sarcoma depends
primarily on tumor histology and the ability to achieve complete tumor resection. Improvements in outcome will require the development of more effective systemic therapies. Cancer 2007;109:1391–6. 2007 American Cancer Society.
KEYWORDS: liver, sarcoma, therapy, surgery.
P
Current address for J. Weitz: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
Address for reprints: Ronald P. DeMatteo, MD,
Memorial Sloan-Kettering Cancer Center, Box
203, 1275 York Ave., New York, NY 10021; Fax:
(212) 639-4031; E-mail: dematter@mskcc.org
Received October 16, 2006; revision received
December 4, 2006; accepted December 21,
2006.
ª 2007 American Cancer Society
rimary sarcomas of the liver are very rare tumors, representing less
than 1% of all hepatic malignancies. Some of the more common hepatic sarcomas are angiosarcoma,1,2 embryonal sarcoma,3,4 leiomyosarcoma,5,6 epithelioid hemangioendothelioma,7,8 fibrosarcoma,9 and
malignant fibrous histiocytoma.10,11 Other sarcomas, such as malignant
solitary fibrous tumor and follicular dendritic cell sarcoma, have also
been found to arise in the liver.12 In infants and children, additional types
such as rhabdomyosarcoma have been described, although these were
excluded from the present report.13,14 In immunocompromised individuals smooth muscle tumors of uncertain malignant potential have been
described that are Epstein-Barr virus (EBV)-driven.15 Primary soft-tissue
sarcomas most commonly originate in the extremities and due to their
prevalence the prognostic factors for these patients have been well documented.16–20 We previously reported our experience with sarcoma metastatic to the liver.21 Due to the rarity of primary hepatic sarcomas, the
natural history, prognostic factors, and optimal management are poorly
characterized. Further complicating the study of primary hepatic sar-
DOI 10.1002/cncr.22530
Published online 21 February 2007 in Wiley InterScience (www.interscience.wiley.com).
CANCER
April 1, 2007 / Volume 109 / Number 7
coma is the diversity of histologic subtypes. In this study
we analyzed our experience over the last 2 decades with
primary hepatic sarcoma in order to define outcome and
prognostic factors.
MATERIALS AND METHODS
Patients
Thirty patients with primary sarcoma of the liver
who were evaluated at Memorial Sloan-Kettering
Cancer Center between January 1981 and December
2004 were identified from the prospective Hepatobiliary and Sarcoma databases. Patients with sarcoma
metastatic to the liver or direct invasion of the liver
by a retroperitoneal sarcoma were not included in
this study. Five other patients with primary carcinosarcoma of the liver were also identified. All pathologic diagnoses were recently reconfirmed.
Patients underwent routine staging using preoperative CT scanning of the chest, abdomen, and pelvis.
Further imaging, such as magnetic resonance imaging
(MRI), positron emission tomography (PET) scan, or
angiography as well as percutaneous biopsy were performed at the discretion of the treating physician. Radiologic studies were reviewed at a multidisciplinary case
management conference held twice weekly. Patients
underwent surgical exploration if all disease was judged
to be completely resectable and if the medical condition of the patient permitted liver resection. Criteria for
inoperability were extrahepatic tumor spread, diffuse
intrahepatic tumor making the patient not a candidate
for complete tumor removal, and impaired liver function precluding the planned hepatic resection. No special liver function tests were used in the context of this
study. Some patients with borderline resectablity by
preoperative imaging also underwent surgical exploration. The use of neoadjuvant, adjuvant, or palliative
chemotherapy was left to the discretion of the treating
physician, taking into account patient preferences, tu-
mor histology, patient comorbidities, and extent of the
tumor.
Patient demographics, tumor characteristics,
treatment, and postoperative course were analyzed.
The completeness of tumor resection (R0-resection
[negative microscopic margins], R1-resection [positive microscopic margin], or R2-resection [gross residual disease]) was recorded.
Statistical Analysis
Statistical computations were performed with the
software package JMP (Cary, NC). The length of follow-up was calculated from the date of hepatectomy
or, in the case of nonoperative management, from
the initial diagnosis at our institution. Survival was
estimated according to the Kaplan-Meier method
and compared using the log-rank test. Statistical significance was defined as P < .05.
RESULTS
Patients With Primary Liver Sarcoma (n = 30)
Demographic and clinical data
Of the 30 patients with primary liver sarcomas, 16 were
(53%) females. The median age was 52 (range, 6–81)
years. Five patients were under the age of 18 (6, 9, 9,
10, and 16 years old). The majority of patients (n ¼ 24,
80%) were Caucasian. None of the patients had known
risk factors for the development of a hepatic sarcoma.
The most common symptom at diagnosis was pain,
which occurred in 19 patients (63%). Five patients had
nonspecific symptoms such as dyspnea or abdominal
discomfort and 6 patients were asymptomatic.
Pathologic factors
The median tumor diameter was 10.5 (range, 2–20) cm.
The median tumor number was 1 (range, 1–13). Twelve
patients (40%) presented with multifocal tumors. A median of 4.5 (range, 1–8) liver segments were involved. The
TABLE 1
Primary Sarcomas of the Liver
Histology
No.
Low-grade
High-grade
Laparotomy R0
Laparotomy R1/R2
No laparotomy
Angiosarcoma
Embryonal sarcoma
Epithelioid hemangioendothelioma
Hemangiopericytoma
Leiomyosarcoma
Pleomorphic MFH
Smooth muscle tumor*
Solitary fibrous tumor
5
5
10
1
2
1
3
3
1
0
10
1
1
0
3
3
4
5
0
0
1
1
0
0
2
5
2
0
0
0
1
1
1
0
2
0
1
1
0
0
2
0
6
1
1
0
2
2
R0 indicates R0 resection; R1/R2, R1 or R2 resection; MFH, malignant fibrous histiocytomas.
*Uncertain malignant potential.
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1392
1393
FIGURE 1. Treatment strategy for 30 patients with primary hepatic sarcomas. EHE indicates epithelioid hemangioendothelioma; *1 patient also
received radiotherapy,
§
5 patients received adjuvant chemotherapy, &2
FIGURE 2. Disease-specific survival of patients with primary hepatic sarcoma (n ¼ 30) stratified according to treatment. EHE indicates epithelioid
patients received chemotherapy.
hemangioendothelioma.
distribution of histologic subtypes is shown in Table 1.
There were 19 (63%) low-grade tumors.
time of last follow-up, 5 patients (17%) had no evidence of disease, 7 (23%) were alive with disease, 13
(44%) had died of disease, 4 patients (13%) had died
of causes unrelated to their malignant disease, and 1
patient (3%) was lost to follow-up.
The 15 patients under the age of 50 had a significantly better 5-year disease-specific survival (67% vs
0% for older patients, P ¼ .005). For the 11 patients
who underwent R0-resection, the 5-year disease-specific survival was 64%. For the 6 patients with epithelioid hemangioendothelioma who were managed
conservatively, the 5-year disease-specific survival
was 67%. In contrast, actuarial 3-year disease-specific
survival was 0% for the other 13 patients in whom
complete resection of the tumor was not possible or
not attempted (P ¼ .0003, Fig. 2).
There were 10 patients with epithelioid hemangioendothelioma and their 5-year disease-specific
survival was 58%. Six of them were managed conservatively with a 5-year disease-specific survival of
67%. Four patients underwent laparotomy; however,
only 2 patients underwent R0-resection and both
died without evidence of tumor recurrence. One
patient underwent R1-resection and died of disease
14 months postoperatively; 1 patient underwent R2resection and was alive with disease 24 months postoperatively.
Treatment
Figure 1 and Table 1 summarize the treatment of the
30 patients. In 14 (47%) patients, surgical exploration
was not attempted, either due to the extent of the
tumor or patient comorbidities (n ¼ 8) or as the patients had diffuse, slow-growing epithelioid hemangioendothelioma (n ¼ 6). Sixteen (53%) patients with
primary hepatic sarcoma underwent surgical exploration with the intention of complete tumor resection.
The following surgical procedures were performed: 7
patients underwent a left or right hepatectomy, 4
patients an extended right hepatectomy, 1 patient a
bisegmentectomy, and 4 patients a laparotomy with
tumor biopsy. Median blood loss was 1160 mL (interquartile range [IQR] 300–2200). The median length of
hospital stay was 11.5 days (IQR 7–15); 7 of 16 (44%)
patients developed postoperative complications, and
the 30-day mortality was 0%. An R0-resection was
achieved in 11 of the 16 patients explored, of whom
2 had received chemotherapy before surgery and 5
patients were given adjuvant chemotherapy. One
patient with an epithelioid hemangioendothelioma
underwent complete macroscopic tumor resection
(right hepatectomy); however, pathologic workup
demonstrated a positive microscopic surgical margin
(R1-resection).
Outcome
The median follow-up for the 30 patients with primary hepatic sarcoma was 20 months (IQR 7–41
months), whereas the median follow-up for surviving
patients was 39 months (IQR 25–66 months). At the
Long-term outcome of patients undergoing R0-resection
(n = 11)
The median follow-up for the 11 patients undergoing
R0-resection was 35 months (IQR 11–63 months),
whereas the median follow-up for surviving patients
was 63 months (IQR 38–160 months). At the time of
the last follow-up, 5 (46%) patients had no evidence
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Primary Liver Sarcoma/Weitz et al.
CANCER
April 1, 2007 / Volume 109 / Number 7
years, with the other patients surviving less than 1
year. The median disease-specific survival for all
patients with carcinosarcoma was 8 months.
DISCUSSION
FIGURE 3. Disease-free survival after R0-resection of hepatic sarcoma
(n ¼ 11) stratified according to histology.
of disease, 3 (27%) had died of disease, and 3 (27%)
patients had died of causes unrelated to their malignant disease. The actuarial 5-year disease-free survival of the 11 patients undergoing complete tumor
resection was 70% and the median has not been
reached. None of the 4 patients with a low-grade tumor developed a tumor recurrence (5-year diseasefree survival 100%) compared with a 5-year diseasefree survival of 57% in patients with a high-grade sarcoma. The patients with primary angiosarcoma had
a particularly poor prognosis, with both patients
developing recurrence and dying within 11 months
(Fig. 3). The actuarial 5-year disease-specific survival
of the 11 patients undergoing complete tumor resection was 64% and the median has not been reached.
Patients with embryonal sarcomas had a 5-year disease-specific survival (and also disease-free survival)
of 80% despite having high-grade tumors.
Patients With Carcinosarcoma of the Liver (n = 5)
Carcinosarcomas were included because their sarcomatoid components may be nearly indistinguishable
from true sarcomas, and they clearly fall in the histologic differential diagnosis of primary liver sarcomas.
Because carcinosarcomas are fundamentally of
epithelial origin, they were analyzed separately from
the 30 primary sarcomas of the liver. Of the 5
patients with primary carcinosarcoma of the liver,
there were 3 female and 2 male patients with a median age of 67 (range, 34–70). One of the patients
had underlying liver cirrhosis. Four patients underwent laparotomy with the intention of tumor resection. R0-resection was achieved in only 1 patient and
this patient died of disease 8 months later. Only 1
patient with carcinosarcoma survived for almost 3
In this study we evaluated the outcome and prognostic factors of patients presenting with primary hepatic sarcomas. There are only a few series in the
literature regarding the management of primary hepatic sarcomas in a mainly adult patient population.22–25 The rarity of this disease is evident by the
existence of only 30 patients with primary hepatic
sarcoma managed at our institution between 1981
and 2004, compared with 331 patients with liver metastases from sarcoma admitted to our institution
during a similar time period.21
In our 30 patients with primary hepatic sarcoma,
we were able to define 3 distinct groups of patients:
patients with complete tumor resection (R0-resection), patients in whom complete resection was not
possible or not attempted, and patients with epithelioid hemangioendothelioma who were managed
conservatively because they had diffuse and indolent
disease. Long-term (>3 years) survival was only possible if R0-resection was achieved, except for patients
with epithelioid hemangioendothelioma. Surgical
resection therefore seems to be the only potentially
curative treatment. In 5 of 16 patients (31%) undergoing surgical exploration a complete tumor resection (R0-resection) could not be achieved. One might
view this as a high R1/R2-resection rate. However, it
is our policy to offer surgical exploration to all
patients without obvious criteria of irresectability or
medical problems precluding major resection. This
aggressive approach is based on the importance of
complete tumor resection in order to reach cure for
the patient and the lack of effective alternative therapies. The development of more accurate imaging
methods may improve patient selection. Hepatic
resection was safe for these patients, with no 30-day
mortality and an acceptable complication rate. As we
and others have reported recently, hepatic resection
has become a safe treatment modality for patients
with hepatic tumors.26 Age and completeness of
resection were significant prognostic factors regarding disease-specific survival, which is consistent with
prognostic factors defined for primary soft-tissue sarcomas of other locations, such as the extremity or
retroperitoneum.17–20 Interestingly, grade did not
appear to be a significant prognostic factor in our
analysis, but the numbers are too small for definitive
conclusion. This is in contrast to other studies
regarding primary hepatic sarcoma and to the find-
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1394
ings in primary soft-tissue sarcoma that arise in
other locations.19,20,23,27 When looking at the patients
in our series who underwent R0-resection, however,
it becomes clear that no patient with a low-grade
sarcoma experienced a tumor recurrence, underlining the relevance of tumor grade in determining the
prognosis of the patient. Patients with high-grade
sarcomas who underwent R0-resection either had
angiosarcoma or embryonal sarcoma. Prognosis for
patients with angiosarcoma was dismal, which is in
accordance with a previous report.28 Patients with
embryonal sarcoma, however, seem to have a particularly favorable outcome, with a 5-year disease-specific survival of 80% in our series. Embryonal
sarcomas usually occur in patients 6 to 10 years of
age and are only uncommon in adults.4,29 In our series 3 of the 5 patients with embryonal sarcoma fell
into the expected age distribution; however, 2 patients presented at the age of 16 and 18. All 5 of our
patients with embryonal sarcoma underwent R0resection followed by systemic chemotherapy. The 5year disease-specific survival of 80% for patients with
embryonal sarcoma is better than that previously
reported, even though other studies have reported
favorable outcomes after resection in combination
with postoperative chemotherapy.29,30 Complete resection followed by systemic chemotherapy might
therefore be the optimal treatment for these patients.
Epithelioid hemangioendothelioma is a distinctive
vascular neoplasm that usually arises in liver, lung, or
bone and can be regarded as a type of low-grade
angiosarcoma. Ten patients with epithelioid hemangioendothelioma were included in our series, with a 5year disease-specific survival of 58%. Of note, 6
patients were managed conservatively and they had a
5-year disease-specific survival of 67%. Our results are
consistent with those of others—hepatic epithelioid
hemangioendothelioma is a malignant tumor with a
favorable, yet unpredictable clinical course in the majority of patients. Treatment options include liver
transplantation, resection, or nonsurgical management, and depend on tumor extent, tumor progression, and patient comorbidities.7,8,31
We treated 5 patients with carcinosarcoma. As
these tumors are fundamentally epithelial tumors in
which the sarcomatoid elements are thought to arise
via transdifferentiation, we analyzed them separately.
In the literature, only a few primary carcinosarcomas
of the liver have been reported.32,33 Whereas the majority of patients previously reported were men with
liver cirrhosis or fibrosis, 3 of the 5 patients in this
report were female patients, and only 1 patient had
underlying liver cirrhosis. Consistent with these other
reports, we found that the prognosis for patients
1395
with primary carcinosarcoma of the liver is poor. The
sarcomatoid regions of carcinosarcomas may be very
difficult to distinguish from true sarcomas, especially
on the basis of a small biopsy specimen.
Our data underscore the importance of tumor
histology and complete tumor resection in the treatment of primary hepatic sarcoma. However, we and
others have shown that recurrence is common.23
Although randomized trials have shown that radiotherapy decreases the local recurrence rate but does
not improve survival for extremity sarcoma,34,35 the
use of radiotherapy is constrained in the liver due to
potential toxicity. Whether adjuvant chemotherapy
improves overall survival in soft-tissue sarcoma
remains debatable, although 1 meta-analysis demonstrated a small benefit.36 Without surgery, chemotherapy can only rarely cure patients with sarcoma.37
As indicated above, adjuvant chemotherapy might
have a role in the treatment of patients with embryonal sarcoma of the liver. New combination regimens
might improve efficacy and decrease side effects, but
whether they improve survival has not been firmly
established.38
We conclude that the outcome of patients with
primary hepatic sarcoma depends primarily on tumor histology and the ability to achieve complete tumor resection. Overall, in order to improve the
outcome for these patients, more effective systemic
therapies are needed.
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