Liver Transplantation in Malignant Primary Hepatic Neoplasms Enrique Moreno Gonzalez, MD, PhD, Ramon G6mez, MD, PhD, Ignacio Garcia MD, Ignacio Gontilez-Pinto, MD, Carmelo Loinaz, MD, Javier Ibafiez, MD, Julio Bercedo, MD, Juan Carlos Palomo, MD, Fermin Palma, MD, Peter Vorwald, MD, Damaso Riaiio, MD, Francisco PQez Cerda, MD, Pedro DBvila, MD, Cesar Cisneros, MD, Vincenzo Maffettone, MD, Marcus Sciadini, BS, Madrid, Spain
Between April 1986 and August 1990, 15 1 liver transplantations were performed at our institution, 16 (11%) of them in 14 patients with primary hepatic tumors. There were 12 hepatocellular carcinomas, 1 angiosarcoma, and 1 Klatskin tumor. None of the tumors was resectable, and there was no preoperative evidence of extrahepatic tumoral extension. Exploratory laparotomy was performed prior to transplantation in three patients and selective embolization of the tumor in six patients. There was no difference in the intraoperative reqnirements for blood or plasma in the patients with hepatic tumors when compared with other transplant reeipients (28.6 f 23.6 units packed red blood cells [PBBCJ versus 20.1 f 17.8 units PRBC, and 17.9 f 12.2 units plasma versus 17.1 f 10.5 units plasma, respectively). Extracorporeal venovenous bypass was used in all but one patient. There was no significant differences in tbe incidence of acute rejection or in the length of hospitalization in these patients when compared with other transplant recipients. All patients received triple immunosuppressive therapy (corticosteroids, asathioprine, and cyclosporin A). Intraoperative mortality was zero. At a mean of 13.3 months’ follow-up (range: 1 to 47 months), 2 of 14 patients had died of sepsis and 1 of terminal cirrhosis (autopsies revealed no evidence of tumor recurrence) ; 3 patients (21% ) had recurrences of the tumor ( 1 in the central nervous system and liver, and the other 2 in the hmg) . One of the three patients with a recurrent tumor is still alive after 16 months. The remaining nine patients (64%) are still alive.
From the Hc~pital 12 de Octubre, General and Digestive Surgery Service C, Liver Transplantation Unit, Madrid, Spain. Requests for repri& should be addrewed to Enrique Moreno Gontilez. MD, PhD. Demrtment of General and Diaestive Surxerv C. Ho&al Ii de &t&e, Ctra. Andalucia Km 5.4, 28041 Ga&id; Spain. Manuscript submitted October 12, 1990, and accepted in revised form March 8, 1991.
M
alignant hepatic tumors may be treated by typical or atypical liver resection if adequate margins of resection are obtained and hepatic insufficiency is avoided [I]. However, there are two groups of patients who are unable to benefit from this type of surgery: those patients with neoplasms occurring in association with cirrhosis and those with interlobar or multiple bilobar tumors [I,Z]. The introduction of liver transplantation into common surgical practice has provided a therapeutic answer to these situations of unresectability [3-51. Despite this, primary hepatic malignancies do not constitute a common indication for hepatic transplant [5j and generally make up less than 10% of cases in most centers [3-51. The interest in this group of potential transplant recip ients is due to the demonstrated capacity for recurrence in a fairly short period of time [I,5]. In fact: the scarcity of donors encourages the selection of patients witbout recurrent hepatic disease [q. It is possible that improvement in patient selection would result in better results in this group of patients for whom no other form of treatment is effective [2,3,5,7,8]. PATIENTS AND METHODS
Of 151 transplants performed between April 1986 and August 1990, 16 (11%) were performed in 14 patients with primary hepatic malignancies that were unresectable by the usual methods of hepatic resection. The other indications for hepatic transplantation are shown in F’igure 1. The average patient age was 48.9 f 9.6 years, and 13 of the 14 patients were men. There were 12 hepatocellular carcinomas in the presence of terminal hepatic cirrhosis (5 positive for hepatitis B surface antigen, two of whom were positive for hepatitis B e antigen at the time of transplant) (Figure 2); 1 tumor of the biliary confluence (Klatskin tumor); and 1 angiosarcoma. The characteristics of the tumors (size, location, histopathologic characteristics, and grade of lymphatic or vascular involvement) are shown in Table I. The absence of extrahepatic tumorous extension was demonstrated by thoracoabdominal computed tomography (CT) (Figure 3), bone scan, and selective arteriography of the celiac trunk (Figure 4). Exploratory laparotomy was performed in three patients and selective embolization of the tumor in six patients. Surgical technique: In these cases, the dissection of the hilar structures in the receptor is carried out to the suprapancreatic level with removal of intervascular/biliary fat and lymphatic tissue for histopathologic study. In
THE AMERICAN JOURNAL OF SURGERY
VOLUME 163 APRIL 1992
395
Othera
I!&
Re-TX
12u
19th
Met.Die.
8. ChOl. 4%
Eil.Atr.
cancer
11%
F. Hop.
10% t:::::::::::::::::::::i :::::::::::j :::::::::::::::::::::::::::::::::::: ::::::::::::::::::::::::::::::::::::: x::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::
Ae-TX
22%
262
F. Hep. Clrrhoalr
152
682 Cirrhoaia
Adults (w124)
102
Children (n=27)
Figure 1. indicationsfor hepatlctranspiantatlon.
Figure 2. Hepatectomy specimen showlng multlfocal hepatocellular carcinoma in the setting of hepatic cirftlosis.
11 patients, extracorporeal venovenous bypass was used (Bio-Med Pump, BioMedicus, Minneapolis, Minnesota) during the anhepatic phase. The reconstructive surgical technique has been described by other investigators [9]. Currently, we close the anterior wall of the portal anastomosis with interrupted 5/O nonresorbable suture material to avoid a reduction in venous flow. The arterial anastomosis is constructed using interrupted 7/O nonresorbable suture material, and the biliary anastomosis is constructed with 3/O long-lasting resorbable suture material (Table II). A Roux-en-Y choledochojejunostomy with a free silicone drainage tube was performed in only one patient (the patient with a Klatskin tumor). 396
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Immunosuppression: Patients received triple therapy (cyclosporin A, corticosteroids, and azathioprine) for 3 months; long-term immunosuppr&ion is achieved with cyclosporin A and corticosteroids alone. Table III lists the guidelines for treatment in the case of acute rejection or renal failure. No other adjuvant means of therapy were used either preoperatively or postoperatively (i.e., radiotherapy or chemotherapy). For postoperative follow-up, the patients were seen weekly, monthly, and later every 2 or 3 months. Special emphasis was placed on the detection of tumor recurrence with periodic checks of tumor markers, echograms, CT scans, and bone scans.
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LIVER TRANSPLANTATION IN HEPATIC NEOPLASMS
RESULTS Lymphatic involvement was found only in the patient with a Klatskin tumor. In the remaining patients, the tumor was confined to the liver (Table I). In one patient, laparotomy revealed three discrete foci of tumor within the cirrhotic liver. The tumors were well encapsulated in 8 of 11 patients (not including the patient with the Klatskin tumor) and 67% of the surviving patients. Of the latter, 89% had moderately or well-differentiated neoplasms. Eleven (79%) of the patients developed acute rejection. Two patients, one with uncontrolled acute rejection (transplant numbers 11 and 12) and the other with chronic rejection (numbers 7 1 and 118), received second transplants. The first patient died of sepsis on the seventh postoperative day, and the second was successfully treated with a second transplant the following year (recurrence of the original Klatskin tumor was not detected in the hepatectomy specimen). Acute rejection was controlled in the other patients. One patient developed cytomegalovirus infection, which was successfully treated with ganciclovir. Tumors recurred in three patients. One tumor recurred in the liver and central nervous system, and the others recurred in the lung (Table IV). One of the latter patients is still alive and almost asymptomatic. Two patients with cirrhosis (positive for hepatitis B surface antigen) and hepatocellular carcinoma developed recurrent viral hepatitis in the graft. In one of these patients, terminal cirrhosis developed in less than 1 year
TABLE
I
Anatomic and Pathologic Characteristics of the Tumors
Transplant No. Type
Size (cm)
Locations
1
HCa
RL
Margins
Differentiation
Lymph Node InCirr- valvehosis ment
Vascular Invokement
16
WEC
PD
+
-
+
4
WEC
WD
+
-
-
WEC
WD
+
-
-
5
HCa
RL
11/12
HCa
RL+
30
HCa
RL
IO
WEC
WD
+
-
-
46
ASarc RL
15
NEC
-
-
-
-
56
HCa
RL+LL
NEC
WD
+
-
-
63
HCa
RL
WEC
WD
+
-
-
65
HCa
RL + LL
WEC
MD
i
-
-
WD
+
+
-
7lIll0
l/6 4.5 614
CCa
-
-
04
HCa
RL
3
WEC
WD
+
-
+
125
HCa
RL+ LL
2
WEC
WD
+
-
-
126
HCa
RL+
-
NEC
PD
+
-
+
143
HCa
RL
3
WEC
WD
+
-
-
147
HCa
RL
2
WEC
WD
f
-
-
HCa =
hepatocellular carcinoma;
LL
-
RL = right lobe;
LL = latt lobe;
CCa
=
NEC = nonencapsulated: WD = well differentiated; MD = moderately differentiated; PD = poorly differentiated; + = involvement; - = no involvement.
cholangiccarcmoma;
L
LL ii/5
ASarc = angiosarcoma;
WEC = well encapsulated;
Flgure 9. Computed tomographic scansofonedtheIraclplontredpientslhatshowtfle~ofama-
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APRIL 1992
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Figure 4. Selective arteriography of ths celiac trunk not only aids @Ijhe diagnosis of ths tumor but also deter: mines the m of vascular involve mentaswellasthepatency.ofthe hepatic artery and portal vein.
TABLE II Surgical Technique, Requirements for Blood, and lschemia Tlme Transplant No.
Anastomoses Arterial (Don-Ret)
Biliary (Don-Ret)
Blood (units)
Cold lschemia (min)
Warm lschemia (min)
1
CT-CHA
c-c
15
390
50
5
CT-CHA
c-c
37
330
55
11112
CT-PHA
c-c
61
390
60
30
PHA-SA
c-c
6
150
55
46
CT-PHA
c-c
46
270
45
56
CT-PHA
c-c
14
270
50
63
CT-PHA
c-c
14
360
50
65
CT-CHA
c-c
16
330
65
71 II 16
CT-PHA
C-J
6
343
65
PHA-PHA
C-C
9
302
64
125
CT-CT
c-c
77
166
69
126
CT-PHA
c-c
40
295
100
143
CT-CT
c-c
4
126
52
147
CT-CT
c-d
52
195
51
64
CC: 92.9% 26.6 t- 23.6
260 ” 66 60.6 + 15.3
Don = donor; Ret = recipient: CT = celisc trunk; PHA = proper hepatic artery; CC = choledochooholcdochostomy; Cl-IA = common hepatic artery; SA = splenlc artery; CJ = cholodochojejunostomy.
398
THE AMERICAN JOURNAL OF SURGERY
(the patient died of hepatic insufficiency). The other patient has asymptomatic chronic persistent hepatitis. One patient developed a benign stenosis in the biliary anastomosis, which was dilated percutaneously. The patient died of uncontrolled septic shock after the percu@neous placement of a pig-tail catheter for biliary decompression (with a bilirubin level of 714 rmol/L). Autopsy revealed no evidence of recurrent tumor 21.5 mbnths after transplantation. The current survival rate is 64% (9 of 14 patients) after an average follow-up of 13.3 months (range: 1 to 47 months). The cumulativcz survival curves (actuarial method) are shown in Figure 5 for the total of 129 patients who received transplants before August 1990 (15 1 transplants performed), for patients who received transplants for hepatic tumors, and for patients with hepatic resections for hepatocarcinoma (with and without cirrhosis) in our surgical service. COMMENTS Until the introduction of liver transplantation into common surgical practice, primary hepatic malignancies that were superimposed on cirrhosis [7] or were bilobar or interlobar could not be surgically treated by either typical or atypical hepatic resection. The absence of effective alternative forms of therapy made these types of malignancies virtually untreatable [I]. Although most liver transplantation centers initially treated patients with unresectable tumors, today these patients do not constitute the principal group of transplant recipients [5], and some surgeons do not consider
VOLUME 163 APRIL 1992
LIVER TRANSPLANTATION
TABLE
III
TABLE
IV Results
Immunosuppressive Therapy Preoperative lntraoperatiie
1st postoperative day
IN HEPATIC NEOPLASMS
None Methylpredniaolone: 500 mg initially, 600 mg after reperfusion followed by 250 mg/6 hr. Methylprednisolone: 1 mgikgll2 hr intravenously. Azathioprine: l-2 mg/kg/24 hr intrave-
ICU Days
Acute Rejection
Hospital Days
1
7
+
51
D4m
5
17
+
58
A47m
11/12
4
_
23
D7d
30
2
+
35
D 17 m Cirrhosis
46
3
_
30
D5m
CNS + hepatitis recurrence
56
6
+
20
A 24 m
(Chronic hepatitis)
63
4
f
39
A 22 m
(Pulmonary recurrence)
65
3
+
32
A22m
711118
7
+
62
A20m
a4
9
+
60
D6m
125
5
+
40
A4m
126
12
_
35
A4m
Transplant No.
Course (d/m)
Cause of Death Pulmanary recurrence
nously.
2nd postoperative day
Add cyclosporine: 1 mg/kg/l2
hr intrave-
nously.
3rd postoperative day
Begin weaning steroids lo a target dose of 0.6 mg/kg/24 hr by day 7 or 6.
On approximatelyday 8. the
T-tube is clamped
cyclosporine A begins at a dose of 4 to 7 mg/kg/24
and administration
(ATG,OKB). Acuterejection tion of 15 mglkglday sara
(ATG,OKl3) are
of oral
hr. If renal failure precludes
tha use of cyciosporine A, more or less specific antilymphocyte
MSF + sepsis
Sara ara used
is treated initially with intravenous bolus administra-
x 3 days. If this treatment is not succtssful. antilymphocyte added.
them suitable candidates for transplantation [5,9]. These patients represented only 7% of the total number of transplant recipients treated by Iwatsuki and colleagues [II], and, in Jenkins’ [S] review of 189 transplant recipients, only 16% had tumors. Approximately 75% of the liver transplant recipients with primary hepatic neoplasms who survive more than 2 months after the procedure develop recurrent tumors [5,22]. However, in considering these results, one must distinguish between two goups: those in whom the tumor constitutes an incidenta! finding and those in whom the tumor has grown considerably and has been diagnosed preoperativell. The survival rate in the first group is similar to or better than that obtained in transplant recip ients without tumors. These findings should encourage transplantation in adequately selected patients with tumors. Such patients should have the following characteristics: (1) small tumors; (2) certain types of tumors in which the clinical course is more favorable, e.g., hepatocellular carcinoma (above all the fibrolamellar variant) and apudomas [4]; and (3) absence of seropositivity for hepatitis B viral antigens. Our survival rate of 64% must be considered acccptable, especially since the tumor was an incidental finding in only one patient, who would have almost certainly died in less than 1 year. Figure 5 illustrates that, in our experience, the actuarial survival of these patients is much lower than the general survival of liver transplant recipients. Survival does appear to be better than that of patients undergoing hepatic resection at 18 months (with cirrhosis) or 4 years (without cirrhosis), although the differences are small and not statistically significant. The results are not the same with all types of tumors. Hepatocelhdar carcinoma is the most frequent type of hepatic neoplasm in the different series (52% to 74%) [5,7j and has the best prognosis, with a survival rate of 30% at 3 years [1?5]. Patients with Klatskin tumors do not seem to benefit from transplantation [5], and the THE AMERICAN
143
2
+
17
Alm
147
14
+
35
Aim
6.624.7
MSF
=
multiple
Septic shock
76.6% 36.4-r 14.5 5dead(at7.1 9 living systems
organ failure;
CNS
=
central
-t6.0m)
nervous
system.
40
I,. H.
20 i
FM 5. Cumulativesurvivalcwves for alI trenspknt recipients (Total TX), transplant recipients with hapatic neopm (TX for Neoplasms),end patientswho utdewent hepetic resectionsfor hepaocellular carcinomewltfl (Hepatectomyce + Cintrosis)and without(bpatectomy Ca) cintrosis. TX = trans#ant; CA = carcinoma.
survival rate in these patients is similar to that of patients treated by hepatic resection [I]. Transplantation in patients with liver cancer offers special problems of surgical strategy, which deserve comJOURNAL
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ment. Should preoperative exploratory laparotomy be performed? When should selective tumorous arterial embolization be performed, and what advantages does it offer? Should a wide lymphadenectomy be carried out with dissection of the bile duct and reconstruction by means of a choledochojejunostomy? The impossibility of planning the time for a liver transplantation in a given patient invalidates the utility of an exploratory laparotomy prior to transplant to determine the tumorous extension and involvement of adjacent structures. This and the availability of CT scans have reduced, in our opinion, the indications for exploratory laparotomy to: (1) cases in which lymph node involvement is demonstrated by CT scan and fine needle biopsy cannot be performed or is inconclusive; (2) cases in which doubt exists about the unresectability of the tumor in patients without cirrhosis; and (3) cases in which vascular structures are possibly involved. Embolixation, which was performed in six patients (including the patient with the angiosarcoma), may be indicated if the tumor mass is large for the purpose of facilitating the hepatectomy in patients with serious portal hypertension. We have not encountered complications with embolization in these patients. However, although the size of the tumor is reduced, the impossibility of predicting the date of transplantation reduces the usefulness of this procedure. The existence of extrahepatic metastases does not always result in the death of the patient, and, curiously, Iwatsuki et al [I I] describe patients in whom the metastases were reduced or completely disappeared after transplantation. Although this is possible, these reports must undoubtedly be treated as isolated cases, and our idea is to proceed with liver transplantation in the absence of extrahepatic invasion. For thii reason, it does not seem justified to extend the lymphadenectomy beyond reasonable limits (to remove perivascular fat and lymphatic tissue) or to resect totally the supraduodenal bile duct. Transplantation is contraindicated when intraoperative lymph node biopsy specimens show malignant neoplasms. In this case, preparation of a second recipient without neoplastic disease permits the graft to be used. Those patients who carry the hepatitis B virus constitute a special case. We have shown that the possibility of developing a new, rapidly progressive hepatitis is more frequent in carriers than in noncarriers. In two of the patients studied, hepatitis recurred, and the poor clinical course of one of these patients is known (death due to cirrhosis). We think that the association of a pattern of viral replication (positive for hepatitis B e antigen and
4.00
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viral DNA) is a contraindication to transplantation and that the carrier state without replication impairs the access of these patients to transplantation, although this latter aspect is still being studied, and it is necessary to monitor closely such treatments as interferon and foscarnet. In conclusion, two factors-(l) careful selection of patients to include those with malignant hepatic neoplasms of reduced size and who are seronegative for hepatitis B virus and (2) the use of alternative postoperative therapeutic modalities [5]-may permit liver transplantation to be the means of curing this disease in patients who currently have no other treatment options available
[71* The authors have taken a reasonable look at liver transplantationfor tumors in this group of patients whose disease is unlikely to respond to other forms of treatment. Control of the neoplasm in an obligatorily immunosuppressedpatient is especially interesting.
REFERENCES 1. Viebahn R, Lauchart W, Becker HD. Surgical therapy of liver and bile duct tumors. Ultraschall Med 1989, 10: 119-22. 2. Scoazec JY, Lamy P, Degott C, et al. Epitheloid hemangioendothelioma of the liver: diagnostic features and role of liver transplantation. Gastroenterology 1988; 94: 1447-53. 3. Arnold JC, O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease: results in 93 consecutive patients. Ann Surg 1988; 207: 373-9. 4. Makowka L, Tzakis AG, Mezzaferro V, et al. Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas. Surg Gynecol Obstet 1989; 168: 107-l 1. 5. Jenkins RL, Pinson CW, Stone MD. Experience with transplantation in the treatment of liver cancer. Cancer Chemother Pharmaco1 1989; 23 Suppl: 104-9. 6. Pichlmayer R, Ringe B, Wittekind C, et al. Liver grafting for malignant liver tumors. Transplant Proc 1989; 21: 2403-5. 7. Ringe B, Wittekind C, Bechstein WB, Benzendahl H, Pichlmayr R. The role of liver transplantation in hepatobiliary malignancy: a retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Arm Surg 1989; 209: 88-98. 8. Funovics JM, Fritsch A, Nerbst F, et al. Primary hepatic cancer: the role of limited resection and total hepatectomy with orthotopic liver replacement. Hepatogastrcenterology 1988; 35: 316-20. 9. Moreno E, Landa I, Calleja J, et al. Resultados de1homotrasplante ortotopico clinico. Gastroenterologia y Hepatologia 1989; 12: 192-201. 10. Powell LW. Liver transplantation: an update for physicians. Aust N Z J Med 1989; 19: 369-77. 11. Iwatsuki S, Gordon R, Shaw B, Starxl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202: 401-7.
VOLUME 163 APRIL 1992
Between April 1986 and August 1990, 15 1 liver transplantations were performed at our institution, 16 (11%) of them in 14 patients with primary hepatic tumors. There were 12 hepatocellular carcinomas, 1 angiosarcoma, and 1 Klatskin tumor. None of the tumors was resectable, and there was no preoperative evidence of extrahepatic tumoral extension. Exploratory laparotomy was performed prior to transplantation in three patients and selective embolization of the tumor in six patients. There was no difference in the intraoperative reqnirements for blood or plasma in the patients with hepatic tumors when compared with other transplant reeipients (28.6 f 23.6 units packed red blood cells [PBBCJ versus 20.1 f 17.8 units PRBC, and 17.9 f 12.2 units plasma versus 17.1 f 10.5 units plasma, respectively). Extracorporeal venovenous bypass was used in all but one patient. There was no significant differences in tbe incidence of acute rejection or in the length of hospitalization in these patients when compared with other transplant recipients. All patients received triple immunosuppressive therapy (corticosteroids, asathioprine, and cyclosporin A). Intraoperative mortality was zero. At a mean of 13.3 months’ follow-up (range: 1 to 47 months), 2 of 14 patients had died of sepsis and 1 of terminal cirrhosis (autopsies revealed no evidence of tumor recurrence) ; 3 patients (21% ) had recurrences of the tumor ( 1 in the central nervous system and liver, and the other 2 in the hmg) . One of the three patients with a recurrent tumor is still alive after 16 months. The remaining nine patients (64%) are still alive.
From the Hc~pital 12 de Octubre, General and Digestive Surgery Service C, Liver Transplantation Unit, Madrid, Spain. Requests for repri& should be addrewed to Enrique Moreno Gontilez. MD, PhD. Demrtment of General and Diaestive Surxerv C. Ho&al Ii de &t&e, Ctra. Andalucia Km 5.4, 28041 Ga&id; Spain. Manuscript submitted October 12, 1990, and accepted in revised form March 8, 1991.
M
alignant hepatic tumors may be treated by typical or atypical liver resection if adequate margins of resection are obtained and hepatic insufficiency is avoided [I]. However, there are two groups of patients who are unable to benefit from this type of surgery: those patients with neoplasms occurring in association with cirrhosis and those with interlobar or multiple bilobar tumors [I,Z]. The introduction of liver transplantation into common surgical practice has provided a therapeutic answer to these situations of unresectability [3-51. Despite this, primary hepatic malignancies do not constitute a common indication for hepatic transplant [5j and generally make up less than 10% of cases in most centers [3-51. The interest in this group of potential transplant recip ients is due to the demonstrated capacity for recurrence in a fairly short period of time [I,5]. In fact: the scarcity of donors encourages the selection of patients witbout recurrent hepatic disease [q. It is possible that improvement in patient selection would result in better results in this group of patients for whom no other form of treatment is effective [2,3,5,7,8]. PATIENTS AND METHODS
Of 151 transplants performed between April 1986 and August 1990, 16 (11%) were performed in 14 patients with primary hepatic malignancies that were unresectable by the usual methods of hepatic resection. The other indications for hepatic transplantation are shown in F’igure 1. The average patient age was 48.9 f 9.6 years, and 13 of the 14 patients were men. There were 12 hepatocellular carcinomas in the presence of terminal hepatic cirrhosis (5 positive for hepatitis B surface antigen, two of whom were positive for hepatitis B e antigen at the time of transplant) (Figure 2); 1 tumor of the biliary confluence (Klatskin tumor); and 1 angiosarcoma. The characteristics of the tumors (size, location, histopathologic characteristics, and grade of lymphatic or vascular involvement) are shown in Table I. The absence of extrahepatic tumorous extension was demonstrated by thoracoabdominal computed tomography (CT) (Figure 3), bone scan, and selective arteriography of the celiac trunk (Figure 4). Exploratory laparotomy was performed in three patients and selective embolization of the tumor in six patients. Surgical technique: In these cases, the dissection of the hilar structures in the receptor is carried out to the suprapancreatic level with removal of intervascular/biliary fat and lymphatic tissue for histopathologic study. In
THE AMERICAN JOURNAL OF SURGERY
VOLUME 163 APRIL 1992
395
Othera
I!&
Re-TX
12u
19th
Met.Die.
8. ChOl. 4%
Eil.Atr.
cancer
11%
F. Hop.
10% t:::::::::::::::::::::i :::::::::::j :::::::::::::::::::::::::::::::::::: ::::::::::::::::::::::::::::::::::::: x::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::
Ae-TX
22%
262
F. Hep. Clrrhoalr
152
682 Cirrhoaia
Adults (w124)
102
Children (n=27)
Figure 1. indicationsfor hepatlctranspiantatlon.
Figure 2. Hepatectomy specimen showlng multlfocal hepatocellular carcinoma in the setting of hepatic cirftlosis.
11 patients, extracorporeal venovenous bypass was used (Bio-Med Pump, BioMedicus, Minneapolis, Minnesota) during the anhepatic phase. The reconstructive surgical technique has been described by other investigators [9]. Currently, we close the anterior wall of the portal anastomosis with interrupted 5/O nonresorbable suture material to avoid a reduction in venous flow. The arterial anastomosis is constructed using interrupted 7/O nonresorbable suture material, and the biliary anastomosis is constructed with 3/O long-lasting resorbable suture material (Table II). A Roux-en-Y choledochojejunostomy with a free silicone drainage tube was performed in only one patient (the patient with a Klatskin tumor). 396
THE AMERICAN JOURNAL OF SURGERY
Immunosuppression: Patients received triple therapy (cyclosporin A, corticosteroids, and azathioprine) for 3 months; long-term immunosuppr&ion is achieved with cyclosporin A and corticosteroids alone. Table III lists the guidelines for treatment in the case of acute rejection or renal failure. No other adjuvant means of therapy were used either preoperatively or postoperatively (i.e., radiotherapy or chemotherapy). For postoperative follow-up, the patients were seen weekly, monthly, and later every 2 or 3 months. Special emphasis was placed on the detection of tumor recurrence with periodic checks of tumor markers, echograms, CT scans, and bone scans.
VOLUME 163 APRIL 1992
LIVER TRANSPLANTATION IN HEPATIC NEOPLASMS
RESULTS Lymphatic involvement was found only in the patient with a Klatskin tumor. In the remaining patients, the tumor was confined to the liver (Table I). In one patient, laparotomy revealed three discrete foci of tumor within the cirrhotic liver. The tumors were well encapsulated in 8 of 11 patients (not including the patient with the Klatskin tumor) and 67% of the surviving patients. Of the latter, 89% had moderately or well-differentiated neoplasms. Eleven (79%) of the patients developed acute rejection. Two patients, one with uncontrolled acute rejection (transplant numbers 11 and 12) and the other with chronic rejection (numbers 7 1 and 118), received second transplants. The first patient died of sepsis on the seventh postoperative day, and the second was successfully treated with a second transplant the following year (recurrence of the original Klatskin tumor was not detected in the hepatectomy specimen). Acute rejection was controlled in the other patients. One patient developed cytomegalovirus infection, which was successfully treated with ganciclovir. Tumors recurred in three patients. One tumor recurred in the liver and central nervous system, and the others recurred in the lung (Table IV). One of the latter patients is still alive and almost asymptomatic. Two patients with cirrhosis (positive for hepatitis B surface antigen) and hepatocellular carcinoma developed recurrent viral hepatitis in the graft. In one of these patients, terminal cirrhosis developed in less than 1 year
TABLE
I
Anatomic and Pathologic Characteristics of the Tumors
Transplant No. Type
Size (cm)
Locations
1
HCa
RL
Margins
Differentiation
Lymph Node InCirr- valvehosis ment
Vascular Invokement
16
WEC
PD
+
-
+
4
WEC
WD
+
-
-
WEC
WD
+
-
-
5
HCa
RL
11/12
HCa
RL+
30
HCa
RL
IO
WEC
WD
+
-
-
46
ASarc RL
15
NEC
-
-
-
-
56
HCa
RL+LL
NEC
WD
+
-
-
63
HCa
RL
WEC
WD
+
-
-
65
HCa
RL + LL
WEC
MD
i
-
-
WD
+
+
-
7lIll0
l/6 4.5 614
CCa
-
-
04
HCa
RL
3
WEC
WD
+
-
+
125
HCa
RL+ LL
2
WEC
WD
+
-
-
126
HCa
RL+
-
NEC
PD
+
-
+
143
HCa
RL
3
WEC
WD
+
-
-
147
HCa
RL
2
WEC
WD
f
-
-
HCa =
hepatocellular carcinoma;
LL
-
RL = right lobe;
LL = latt lobe;
CCa
=
NEC = nonencapsulated: WD = well differentiated; MD = moderately differentiated; PD = poorly differentiated; + = involvement; - = no involvement.
cholangiccarcmoma;
L
LL ii/5
ASarc = angiosarcoma;
WEC = well encapsulated;
Flgure 9. Computed tomographic scansofonedtheIraclplontredpientslhatshowtfle~ofama-
THE AMERICAN
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Figure 4. Selective arteriography of ths celiac trunk not only aids @Ijhe diagnosis of ths tumor but also deter: mines the m of vascular involve mentaswellasthepatency.ofthe hepatic artery and portal vein.
TABLE II Surgical Technique, Requirements for Blood, and lschemia Tlme Transplant No.
Anastomoses Arterial (Don-Ret)
Biliary (Don-Ret)
Blood (units)
Cold lschemia (min)
Warm lschemia (min)
1
CT-CHA
c-c
15
390
50
5
CT-CHA
c-c
37
330
55
11112
CT-PHA
c-c
61
390
60
30
PHA-SA
c-c
6
150
55
46
CT-PHA
c-c
46
270
45
56
CT-PHA
c-c
14
270
50
63
CT-PHA
c-c
14
360
50
65
CT-CHA
c-c
16
330
65
71 II 16
CT-PHA
C-J
6
343
65
PHA-PHA
C-C
9
302
64
125
CT-CT
c-c
77
166
69
126
CT-PHA
c-c
40
295
100
143
CT-CT
c-c
4
126
52
147
CT-CT
c-d
52
195
51
64
CC: 92.9% 26.6 t- 23.6
260 ” 66 60.6 + 15.3
Don = donor; Ret = recipient: CT = celisc trunk; PHA = proper hepatic artery; CC = choledochooholcdochostomy; Cl-IA = common hepatic artery; SA = splenlc artery; CJ = cholodochojejunostomy.
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THE AMERICAN JOURNAL OF SURGERY
(the patient died of hepatic insufficiency). The other patient has asymptomatic chronic persistent hepatitis. One patient developed a benign stenosis in the biliary anastomosis, which was dilated percutaneously. The patient died of uncontrolled septic shock after the percu@neous placement of a pig-tail catheter for biliary decompression (with a bilirubin level of 714 rmol/L). Autopsy revealed no evidence of recurrent tumor 21.5 mbnths after transplantation. The current survival rate is 64% (9 of 14 patients) after an average follow-up of 13.3 months (range: 1 to 47 months). The cumulativcz survival curves (actuarial method) are shown in Figure 5 for the total of 129 patients who received transplants before August 1990 (15 1 transplants performed), for patients who received transplants for hepatic tumors, and for patients with hepatic resections for hepatocarcinoma (with and without cirrhosis) in our surgical service. COMMENTS Until the introduction of liver transplantation into common surgical practice, primary hepatic malignancies that were superimposed on cirrhosis [7] or were bilobar or interlobar could not be surgically treated by either typical or atypical hepatic resection. The absence of effective alternative forms of therapy made these types of malignancies virtually untreatable [I]. Although most liver transplantation centers initially treated patients with unresectable tumors, today these patients do not constitute the principal group of transplant recipients [5], and some surgeons do not consider
VOLUME 163 APRIL 1992
LIVER TRANSPLANTATION
TABLE
III
TABLE
IV Results
Immunosuppressive Therapy Preoperative lntraoperatiie
1st postoperative day
IN HEPATIC NEOPLASMS
None Methylpredniaolone: 500 mg initially, 600 mg after reperfusion followed by 250 mg/6 hr. Methylprednisolone: 1 mgikgll2 hr intravenously. Azathioprine: l-2 mg/kg/24 hr intrave-
ICU Days
Acute Rejection
Hospital Days
1
7
+
51
D4m
5
17
+
58
A47m
11/12
4
_
23
D7d
30
2
+
35
D 17 m Cirrhosis
46
3
_
30
D5m
CNS + hepatitis recurrence
56
6
+
20
A 24 m
(Chronic hepatitis)
63
4
f
39
A 22 m
(Pulmonary recurrence)
65
3
+
32
A22m
711118
7
+
62
A20m
a4
9
+
60
D6m
125
5
+
40
A4m
126
12
_
35
A4m
Transplant No.
Course (d/m)
Cause of Death Pulmanary recurrence
nously.
2nd postoperative day
Add cyclosporine: 1 mg/kg/l2
hr intrave-
nously.
3rd postoperative day
Begin weaning steroids lo a target dose of 0.6 mg/kg/24 hr by day 7 or 6.
On approximatelyday 8. the
T-tube is clamped
cyclosporine A begins at a dose of 4 to 7 mg/kg/24
and administration
(ATG,OKB). Acuterejection tion of 15 mglkglday sara
(ATG,OKl3) are
of oral
hr. If renal failure precludes
tha use of cyciosporine A, more or less specific antilymphocyte
MSF + sepsis
Sara ara used
is treated initially with intravenous bolus administra-
x 3 days. If this treatment is not succtssful. antilymphocyte added.
them suitable candidates for transplantation [5,9]. These patients represented only 7% of the total number of transplant recipients treated by Iwatsuki and colleagues [II], and, in Jenkins’ [S] review of 189 transplant recipients, only 16% had tumors. Approximately 75% of the liver transplant recipients with primary hepatic neoplasms who survive more than 2 months after the procedure develop recurrent tumors [5,22]. However, in considering these results, one must distinguish between two goups: those in whom the tumor constitutes an incidenta! finding and those in whom the tumor has grown considerably and has been diagnosed preoperativell. The survival rate in the first group is similar to or better than that obtained in transplant recip ients without tumors. These findings should encourage transplantation in adequately selected patients with tumors. Such patients should have the following characteristics: (1) small tumors; (2) certain types of tumors in which the clinical course is more favorable, e.g., hepatocellular carcinoma (above all the fibrolamellar variant) and apudomas [4]; and (3) absence of seropositivity for hepatitis B viral antigens. Our survival rate of 64% must be considered acccptable, especially since the tumor was an incidental finding in only one patient, who would have almost certainly died in less than 1 year. Figure 5 illustrates that, in our experience, the actuarial survival of these patients is much lower than the general survival of liver transplant recipients. Survival does appear to be better than that of patients undergoing hepatic resection at 18 months (with cirrhosis) or 4 years (without cirrhosis), although the differences are small and not statistically significant. The results are not the same with all types of tumors. Hepatocelhdar carcinoma is the most frequent type of hepatic neoplasm in the different series (52% to 74%) [5,7j and has the best prognosis, with a survival rate of 30% at 3 years [1?5]. Patients with Klatskin tumors do not seem to benefit from transplantation [5], and the THE AMERICAN
143
2
+
17
Alm
147
14
+
35
Aim
6.624.7
MSF
=
multiple
Septic shock
76.6% 36.4-r 14.5 5dead(at7.1 9 living systems
organ failure;
CNS
=
central
-t6.0m)
nervous
system.
40
I,. H.
20 i
FM 5. Cumulativesurvivalcwves for alI trenspknt recipients (Total TX), transplant recipients with hapatic neopm (TX for Neoplasms),end patientswho utdewent hepetic resectionsfor hepaocellular carcinomewltfl (Hepatectomyce + Cintrosis)and without(bpatectomy Ca) cintrosis. TX = trans#ant; CA = carcinoma.
survival rate in these patients is similar to that of patients treated by hepatic resection [I]. Transplantation in patients with liver cancer offers special problems of surgical strategy, which deserve comJOURNAL
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ment. Should preoperative exploratory laparotomy be performed? When should selective tumorous arterial embolization be performed, and what advantages does it offer? Should a wide lymphadenectomy be carried out with dissection of the bile duct and reconstruction by means of a choledochojejunostomy? The impossibility of planning the time for a liver transplantation in a given patient invalidates the utility of an exploratory laparotomy prior to transplant to determine the tumorous extension and involvement of adjacent structures. This and the availability of CT scans have reduced, in our opinion, the indications for exploratory laparotomy to: (1) cases in which lymph node involvement is demonstrated by CT scan and fine needle biopsy cannot be performed or is inconclusive; (2) cases in which doubt exists about the unresectability of the tumor in patients without cirrhosis; and (3) cases in which vascular structures are possibly involved. Embolixation, which was performed in six patients (including the patient with the angiosarcoma), may be indicated if the tumor mass is large for the purpose of facilitating the hepatectomy in patients with serious portal hypertension. We have not encountered complications with embolization in these patients. However, although the size of the tumor is reduced, the impossibility of predicting the date of transplantation reduces the usefulness of this procedure. The existence of extrahepatic metastases does not always result in the death of the patient, and, curiously, Iwatsuki et al [I I] describe patients in whom the metastases were reduced or completely disappeared after transplantation. Although this is possible, these reports must undoubtedly be treated as isolated cases, and our idea is to proceed with liver transplantation in the absence of extrahepatic invasion. For thii reason, it does not seem justified to extend the lymphadenectomy beyond reasonable limits (to remove perivascular fat and lymphatic tissue) or to resect totally the supraduodenal bile duct. Transplantation is contraindicated when intraoperative lymph node biopsy specimens show malignant neoplasms. In this case, preparation of a second recipient without neoplastic disease permits the graft to be used. Those patients who carry the hepatitis B virus constitute a special case. We have shown that the possibility of developing a new, rapidly progressive hepatitis is more frequent in carriers than in noncarriers. In two of the patients studied, hepatitis recurred, and the poor clinical course of one of these patients is known (death due to cirrhosis). We think that the association of a pattern of viral replication (positive for hepatitis B e antigen and
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THE AMERICAN JOURNAL OF SURGERY
viral DNA) is a contraindication to transplantation and that the carrier state without replication impairs the access of these patients to transplantation, although this latter aspect is still being studied, and it is necessary to monitor closely such treatments as interferon and foscarnet. In conclusion, two factors-(l) careful selection of patients to include those with malignant hepatic neoplasms of reduced size and who are seronegative for hepatitis B virus and (2) the use of alternative postoperative therapeutic modalities [5]-may permit liver transplantation to be the means of curing this disease in patients who currently have no other treatment options available
[71* The authors have taken a reasonable look at liver transplantationfor tumors in this group of patients whose disease is unlikely to respond to other forms of treatment. Control of the neoplasm in an obligatorily immunosuppressedpatient is especially interesting.
REFERENCES 1. Viebahn R, Lauchart W, Becker HD. Surgical therapy of liver and bile duct tumors. Ultraschall Med 1989, 10: 119-22. 2. Scoazec JY, Lamy P, Degott C, et al. Epitheloid hemangioendothelioma of the liver: diagnostic features and role of liver transplantation. Gastroenterology 1988; 94: 1447-53. 3. Arnold JC, O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease: results in 93 consecutive patients. Ann Surg 1988; 207: 373-9. 4. Makowka L, Tzakis AG, Mezzaferro V, et al. Transplantation of the liver for metastatic endocrine tumors of the intestine and pancreas. Surg Gynecol Obstet 1989; 168: 107-l 1. 5. Jenkins RL, Pinson CW, Stone MD. Experience with transplantation in the treatment of liver cancer. Cancer Chemother Pharmaco1 1989; 23 Suppl: 104-9. 6. Pichlmayer R, Ringe B, Wittekind C, et al. Liver grafting for malignant liver tumors. Transplant Proc 1989; 21: 2403-5. 7. Ringe B, Wittekind C, Bechstein WB, Benzendahl H, Pichlmayr R. The role of liver transplantation in hepatobiliary malignancy: a retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Arm Surg 1989; 209: 88-98. 8. Funovics JM, Fritsch A, Nerbst F, et al. Primary hepatic cancer: the role of limited resection and total hepatectomy with orthotopic liver replacement. Hepatogastrcenterology 1988; 35: 316-20. 9. Moreno E, Landa I, Calleja J, et al. Resultados de1homotrasplante ortotopico clinico. Gastroenterologia y Hepatologia 1989; 12: 192-201. 10. Powell LW. Liver transplantation: an update for physicians. Aust N Z J Med 1989; 19: 369-77. 11. Iwatsuki S, Gordon R, Shaw B, Starxl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202: 401-7.
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