results of liver transplantation in the treatment of metastatic

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ANNALS OF SURGERYVol. 225, No. 4, 355-364© 1997 Lippincott-Raven Publishers

Results of Liver Transplantation inthe Treatment of MetastaticNeuroendocrine Tumors

A 31-Case French Multicentric Report

Y. Patrice Le Treut, M.D.,* Jean R. Delpero, M.D.,* Bertrand Dousset, M.D.,tDaniel Cherqui, M.D.J Philippe Segol, M.D.,§ Georges Mantion, M.D.,IILaurent Hannoun, M.D.,¶ Guy Benhamou, M.D.,# Bernard Launois, M.D.,**Olivier Boillot, M.D.,tt Jacques Domergue, M.D.,#tand Henri Bismuth, M.D., F.A.C.S. (Hon)§§

From the Department of Surgery, * Hopital de La Conception, Marseilles; CliniqueChirurgicale, t Hopital Cochin, Paris; Department of Surgery, Hopital Henri-Mondor,Creteil; Department of Digestive Surgery, § Centre Hospitalier de Caen; Department ofDigestive and Vascular Surgery, 11 Centre Hospitalier de Besan9on; Department of DigestiveSurgery, Hopital Saint Antoine, Paris; Department of Surgery,# Hopital Bichat-ClaudeBernard, Paris; Department of Surgery,** Hopital Pontchailfou, Rennes; Liver TransplantUnit, tt Hopital Edouard Herriot, Lyon; Department of Digestive Surgery, 4t Hopital SaintEloi, Montpellier; and Hepato-Biliary Center, §§ Hopital Paul Brousse, Villejuif, France

ObjectiveThe purpose of this study was to assess the value and timing of orthotopic livertransplantation (OLT) in the treatment of metastatic neuroendocrine tumors (NET).

Summary Background DataLiver metastasis from NET seems less invasive than other secondary tumors. Thisobservation suggests that OLT may be indicated when other therapies become ineffective.However, the potential benefit of this highly aggressive procedure is difficult to assess dueto the scarcity and heterogeneity of NET.

MethodsA retrospective multicentric study was carried out, including all cases of OLT for NETperformed in France between 1989 and 1994. There were 15 cases of metastatic carcinoidtumor and 16 cases of islet cell carcinomas. Hormone-related symptoms were present in

16 cases (55%). Only 5 patients (16%) had no previous surgical or medical therapy beforeOLT. Median delay from diagnosis of liver metastasis and OLT was 19 months (range, 2 to

120).

ResultsThe primary tumor was removed at the time of OLT in 11 cases, by upper abdominalexenteration in 7 cases and the Whipple resection in 3. Actuarial survival rate after OLT was

355

356 Le Treut and Others

59% at 1 year, 47% at 3 years, and 36% at 5 years. Survival rates were significantly higherfor metastatic carcinoid tumors (69% at 5 years) than for noncarcinoid apudomas (8% at 4years), because of higher tumor- and non-tumor-related mortality rates for the latter.

ConclusionOLT can achieve control of hormonal symptoms and prolong survival in selected patientswith liver metastasis of carcinoid tumors. It does not seem indicated for other NET.

Orthotopic liver transplantation (OLT) has been pro-

gressively abandoned for management of most hepaticmetastasis because the unacceptably high recurrence ratedoes not justify the cost of the procedure and utilization ofscarce donor organs."2 In cases of neuroendocrine tumors(NET), metastases are frequently confined to the liver andusually slow-growing, possibly characterizing them as tu-mors of a less agressive nature than other secondaries.3However, quality of life is often poor due to pain anddebility related to hepatomegaly and/or hormone produc-tion, and hepatic metastasis is the cause of death in thesepatients. Conventional partial hepatectomy is seldom pos-

sible since hepatic metastases are multifocal and bilateralin 90% of cases.4 Cytoreductive surgery or "debulking"achieves 5-year survival in nearly 50% of cases, but thenumber of eligible patients is low.5-7 In general, palliativetreatments have been proposed for these patients, includ-ing systemic or intraarterial chemotherapy,3'8 induced he-patic ischemia,4 antihormone therapy using somatostatinanalogue,9 and more recently interferon therapy,'0 but sur-

vival rarely exceeds 25 to 35% at 5 years.3'4" For thesereasons, patients with metastatic NET are currently under"favorable consideration" for OLT.2Assessment of the benefits of OLT in the treatment of

metastatic NET is difficult because this entity is rare. Inthis regard, it should be emphasized that the term "neuro-endocrine" is a generic denomination for disparate condi-tions'2 that can be divided into two groups, i.e., carcinoidtumors of the bronchial tree or digestive tract and noncar-

cinoid apudomas (NCA), essentially pancreatic islet cellcarcinomas.34 Failure to distinguish between carcinoidsand NCA makes it difficult to interpret the results of somestudies. The small number of NET also accounts for thefact that nearly all previous data come from single case

reports or small unicentric series 13-25 with limited follow-up. Similarly, the three largest series reported by groups inHanover,2 King's College,26 and Pittsburgh27 have limited

follow-up. The purpose of this retrospective study of the

Part of this work was presented at the Joumres Francophones de Patho-logie Digestive, Nantes, France, March 25-29, 1995.

Address correspondence and reprint requests to Dr. Y. Patrice Le Treut,Service de Chirurgie, H9pital de La Conception, 147 BoulevardBaille, 13385 Marseille Cedex 5, France.

Accepted for publication July 1, 1996.

results of a multicentric French series was to define therole and timing for OLT in the treatment of metastaticNET.

PATIENTS AND METHODS

Data Collection

Data were collected retrospectively from the personsin charge of the 22 liver transplantation centers in France.All centers responded. Eleven centers reported no OLTfor NET, one reported eight cases, two reported five cases,one reported three cases, three reported two cases, andfour reported one case. Details concerning some of theeight cases from Cochin Hospital in Paris have been pre-viously described.28 For each patient, the following datawas compiled: pretransplant disease and treatment his-tory, transplantation procedures, and follow-up data, in-cluding the type and delay of recurrrences and cause ofdeaths.

Statistical Methods

Data were expressed as medians (range) due to thesmall population. Comparisons were made using the non-parametric Mann-Withney U, the chi-square, and theFisher tests. Survival curves were generated using theKaplan Meier method and were compared using the Lo-grank test. A p value of <0.05 was considered statisticallysignificant. Follow-up evaluation was made on June 30,1995

Patients and Pretransplant DiseaseHistoryThe 31 OLT for metastatic NET were performed be-

tween March 1989 and September 1994 (Table 1). Therewere 14 women and 17 men, with a mean age of 45 years(range, 26 to 60) at the time of OLT. In 15 cases, theprimary tumor was a carcinoid: located in the ileum in 7cases, lung in 3 cases, stomach in 2 cases, sigmoid in 1case, rectum in 1 case, and pancreas in 1 case. In 16cases, the tumor was a NCA: gastrinoma in 7 cases (in-cluding one gastrinoma-insulinoma and one gastrinoma-carcinoid that was part of a multiple endocrine neoplasia

Ann. Surg. * April 1997

Transplantation for Metastatic Neuroendocrine Tumors 357

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type 1 (MEN-1) syndrome), glucagonoma in 1 case, andnonfunctioning islet cell carcinoma in 8 cases (includingtwo that could be considered as subclinical glucagonomaand one as subclinical insulinoma).NET was associated with symptomatic hormonal syn-

drome (gastrointestinal, metabolic, or vasomotor) in 16cases, or 55%. Typical carcinoid syndrome was observedin 8 of 15 cases, or 53%. Diarrhea and/or recurrent gastro-duodenal ulcers were observed in 7 of 16 NCA, or 44%.Hypercalcemia was observed in two cases: diabetes inone case and severe paraneoplastic Cushing syndrome inone case. In 18 cases, there was an abnormal elevationof plasma levels of the following peptides and/or amines:serotonin in 10 cases, gastrin in 5 cases (including 4associated with elevated ACTH, insulin, parathyroid hor-mone, and prolactin), glucagon in 2 cases, and parathyroidhormone in 1 case.

Resection of the primary tumor had been performedprior to OLT in 17 cases, or 54%, Resection was per-formed more often in patients with carcinoid tumors (11of 15 cases, or 73%) than NCA (6 of 16 cases, or 38%)(p < 0.05). The procedures used are summarized in Table1. One or more hepatectomies for metastasis had beenperformed in four patients, including three complete sin-gle stage resections and one incomplete two-stage resec-tion. In 11 cases, resection of the primary tumor wasperformed at the time of OLT. In two cases, the primarytumor was identified only after OLT: one nonsecretingcarcinoid (8 mm) on a Meckel's diverticulum that wasresected at 6 months after OLT and one nonfunctioningapudoma (7 mm) in the head of the pancreas resected 18months after OLT. In the remaining case, the primarygastrinoma was probably a positive lateroduodenal lymphnode that was removed during OLT.

In five cases, hepatic metastasis was diagnosed beforedetection of the primary tumor, with a delay of 6, 18, 36,60, and 120 months. In 22 cases, hepatic metastasis waspresent at the time of diagnosis of the primary tumor. Infour cases, hepatic metastasis occured after the diagnosisof the primary tumor, with a delay of 18, 24, 25, and 72months. Hepatic metastasis was multiple and bilateral in27 cases, and the remaining four cases involved hepaticrecurrence after previous hepatectomy. Systemic or in-traarterial chemotherapy had been administered prior toOLT in 23 cases, or 74%. The most common protocolwas a 5FU-streptozotocine combination. Most patientsreceived specific hormonal inhibitors using octreotide(carcinoids) or omeprazole (gastrinomas). Five patients,or 16%, did not undergo surgery or chemotherapy priorto OLT.The median time from diagnosis of hepatic metastasis

to OLT was 19 months (range, 2-120). There was nosignificant difference in the median diagnosis-to-OLT de-lay for patients with carcinoid tumors (21 months, with

a range of 2 to 120) and patients with NCA (19 months,with a range of 2 to 108). The indication for transplanta-tion was hormonal syndrome poorly controlled by medi-cal treatment in 11 cases (35%) (carcinoid syndrome in7 cases and diarrhea, ulcers, hypercalcemia, or some com-bination thereof in the other 4 cases). The median delayfrom diagnosis of hepatic metastasis to OLT in this groupwas 24 months. In another 11 cases (35%), transplantationwas indicated by pain or debility associated with tumorbulk. The median delay from diagnosis of hepatic metas-tasis to OLT in this group was 21 months. In eight cases,OLT was performed with the intent to cure patients withstable bilobar invasion without hormonal syndrome ordebilitating hepatomegaly, including one patient whosepretransplant diagnosis was fibrolamellar carcinoma. Themedian delay from diagnosis of hepatic metastasis to OLTin this group was 10 months. In the remaining patient,OLT was performed in emergency for active varicealbleeding related to secondary sclerosing cholangitis withportal hypertension due to chemoembolization.

RESULTS

Transplantation Procedures

Total hepatectomy with lymphadenectomy of thehepatoduodenal ligament (or beyond) was performedin all cases (Table 2). Extrahepatic resection was per-formed in 14 cases, or 45%: en bloc diaphragmaticresection in 3 cases and concomitant resection of theprimary tumor in 11 cases, including ileal resectionin one case, Whipple resection in 3 cases, and upperabdominal exenteration with removal of the stomach,spleen, duodenopancreatic complex, and variableamounts of the colon in 7 cases. After upper abdomi-nal exenteration, liver replacement was associatedwith duodenum pancreas en bloc ("cluster proce-dure"29) in three cases and intraportal injection ofpancreatic islet cells30 in one case. Biliary reconstruc-tion was achieved by bilioenteric anastomosis in 17cases and biliobiliary anastomosis in 11 cases. Biliaryanastomosis was not performed in the three cases in-volving composite hepatic duodenal and pancreaticgraft. Venovenous bypass was used in 18 cases, or58%.The median duration of cold ischemia was 10 hours

(range, 5.6 to 20). Overall median procedure durationwas 10 hours (range, 5.5 to 20). Median procedureduration was 9 hours (range, 5.5 to 17) for simplehepatectomy (21 cases) and 11 hours (range, 8 to 20)for hepatectomy associated with extensive visceral re-section as in the Whipple resection or upper abdominalexenteration (10 cases). Procedure duration was 10,12, and 14.5 hours for the three cases of composite

Ann. Surg. * Apnl 1997

Transplantation for Metastatic Neuroendocrine Tumors

Table 2. OPERATIVE DATA AND CLINICAL OUTCOME

Surgery inCase Addition to Specimen Metastatic Major Surgical and Medical Postoperative Site of Follow-No. the OLT* Weight (g) LN Complications Stay (days) Recurrence Status up (mo)

1 None2 None3 Upper abdominal

exenterationt4 None5 Diaphragmatic

resection6 Ileal resection7 None

8 None9 None

10 Upper abdominalexenteration



13 Upper abdominalexenterationt

1 4 None


16 Upper abdominalexenterationt

1 7 Diaphragmaticresection

18 None

1 9 None20 None

21 None22 None23 None24 Whipple resection25 None

26 None

27 None

28 None29 Diaphragmatic

resection30 Whipple resection

31 Whipple resection

139054004280

2750

Yes

2900 Mesenteric6750 Hilar

- No13000 No

7500 No

Subcapsular hematoma

Acute pancreatitis, peritonealbleeding

Peritoneal bleeding, PVthrombosis, re-OLT (Dl 2)

Peritoneal bleeding, HAaneurysm

Chronic rejection: re-OLT at 5mo

5100 Yes Ileocolic anastomotic fistula

- - Perftoneal bleeding, re-OLT forPNF (D4)

1400 No Peritoneal bleeding, acutepancreatitis

3300 - Peritoneal bleeding, CMVpneumonitis

4000 No Esojejunal anastomotic fistula

1320 Yes, 13/15

- Celiac

8900 Hilar

1412 No- Duodenal

3350 Hilar1233 No1800 No2580 Yes

1620

2200

Periaortic

Yes, 13

No

Enteric fistula, unexplainedsepsis

Chronic rejection: re-OLT at 7mo

Peritoneal bleedingBiloma

Acute rejection (OKT3)Peritoneal bleeding, PVthrombosis

HA thrombosis, biliary stricture,acute rejection (FK 506)

2800 Yes Pancreatic fistula, digestivehemorrhage

4500 Yes Acute rejection (OKT3, FK 506)

2625

Died, 18

22Died, 83

4737

1532

30

76

Died, 6

Died, 6

28

57

Died, 74

24

30

2116

39452147

Died, 12

15

22

2633

Bone (spine)

Rapid generalization

Mesenteric LNRapid generalization

Bone, liver

bone (spine)

Bone, generalization

Bone, ovaries,abdominal LN

Periaortic LN

Bone, lungsPeritoneum, liver

Peritoneum(resected)

35

45

OLT = orthotopic liver transplantation; PV = portal vein; HA = hepatic artery; PNF = primary nonfunction; LN = lymph nodes.* Except for node dissection.t Cases with duodenum pancreas graft.

hepatic duodenal and pancreatic graft. Median transfu-sion requirements were 10 U of red blood cells (range,0 to 130) and 20 U of plasma (range, 0 to 104) in theoverall population, 6 U of red blood cells (range, 0 to45) and 12 U of plasma (range, 0 to 56) in the groupthat underwent simple hepatectomy, and 22 U of redblood cells (range, 5 to 130) and 50 U of plasma(range, 16 to 104) in the group in which hepatectomywas associated with resection of adjacent organs otherthan the diaphragm or small intestine.

The weight of the surgical specimens was indicated in23 of the 31 cases. Overall median weight was 2896 g(range, 1230 to 13,000). The median weight of the surgi-cal specimen was 2500 g in patients transplanted for hor-monal syndrome, 5400 g in patients transplanted mainlyfor hepatomegaly, and 1980 g for patients transplantedfor other reasons. There was lymph node involvement ofthe hepatoduodenal ligament or beyond in 13 cases, and

no lymph node involvement in 10 cases. In the remainingeight cases, this information was not mentioned.

AliveDiedDied

DiedDied

AliveDied

AliveAlive

Died

7741

1

63

702

7070

30

Died

Died

Died

Alive

Died

Died

Died

0

0

63

10

3

16

51

498

39371770

32

23

2321

5

10

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AliveDied

DiedAliveDiedDiedDied

Alive

Alive

AliveAlive

Died

Alive

359Vol. 225 * No. 4


Follow-Up

Immunosuppression included a double regimen usingcyclosporin and corticosteroids or a triple regimen usingcyclosporin, corticosteroids, and azathioprine in all pa-tients except one liver-pancreas recipient in whom pro-phylactic OKT3 was used (Table 2). Acute corticosteroid-resistant rejection occurred in three cases requiring OKT3and/or FK 506. Chronic rejection occurred in two casesrequiring retransplantation at 5 and 7 months postopera-tively.

Postoperative Mortality and Morbidity

Six patients, or 19%, died after surgery. The cause ofdeath was persistent intraabdominal hemorrhage in fiveof six cases-associated with acute pancreatitis in twocases, thrombosis of the portal vein in two cases, andprimary nonfunction of the graft in one case. In the re-maining patient, death resulted from disseminated bacte-rial and viral infection. The postoperative mortality ratewas 7% for carcinoid tumors (1 of 15 cases) and 31% forNCA (5 of 16 cases). This difference was not significant.Postoperative mortality was 57% (4 of 7 cases) in patientswho underwent upper abdominal exenteration, and 100%(3 of 3 cases) in patients who underwent duodenum-pan-creas replacement. One or more major surgical complica-tions occurred in 15 patients, usually requiring furthersurgery. In two of these patients, retransplantation forearly graft failure was performed at days 4 and 12. Majorcomplications occurred in 7 of the 10 cases, or 70%,involving major extrahepatic resection (exenteration orWhipple resection) and in 8 of the 21 cases, or 38%,involving hepatectomy alone (NS). The median durationof postoperative stay was 29 days (range, 15 to 76).

Long-Term Results

Twenty-five patients were discharged. None was lostto follow-up. Twelve patients (3 with carcinoids and 9with NCAs) died after discharge. The cause of death wasa delayed technical or other nontumor complications in 4cases, including two fatal hypoglycemic events associatedwith severe malnutrition at months 4 and 10 after supra-mesocolic exenteration, one massive digestive hemor-rhage due to rupture of the splenic artery 5 months afterOLT combined with Whipple resection, and one hepaticartery thrombosis after retransplantation at postoperativemonth 7 for chronic rejection. One death due to diabeticcoma with intravascular coagulopathy occurred 30months after exenteration for gastrinoma in a patient withmultiple spine metastases. Thus, all seven patients whounderwent upper abdominal exenteration died from im-mediate or delayed procedure-related complications.Seven patients died of tumor recurrence within 2 to 41months after OLT. Bone metastases were observed in

100

-

40

._4

UX

v-

0

r.4-u

S

u

S;

0 12 24 36 48 60months after transplantation

72 84

Figure 1. Survival after OLT for metastatic neuroendocrine tumors.NED = nonevidence of disease; AWD = alive with disease. Carcinoidsvs. noncarcinoid apudomas; p < 0.001.

almost all cases associated with liver, lymph node, andperitoneal involvement. It should be emphasized that sixof the eight patients who died from or with tumor recur-rence presented metastatic NCA.

In mid 1995, 13 patients (11 with carcinoids and 2 withNCAs) were living. Eight had no biochemical or imagingevidence of recurrent disease at follow-ups of 10 to 77months. The remaining 5 patients with follow-ups of 23to 70 months had evidence of metastasis, including boneand spine involvement in 3 cases, abdominal lymph nodeinvolvement in 1 case, and peritoneal involvement(treated by debulking 15 months after OLT) in 1 case.The diagnosis in four of these five patients was carcinoidtumors.

Overall Patient Survival

Median follow-up in the 31 patients of this series was57 months (range, 10-77). Median survival was 30months after transplantation. Actuarial survival was 58%,51%, 47%, 36%, and 36% at 1 to 5 years, respectively(Fig. 1). Five patients survived >60 months, includingtwo who were disease-free in mid- 1995. The survival rateat 5 years after diagnosis of liver invasion was 57%.Overall disease-free survival was 45%, 29%, and 17% at1, 3, and 5 years after OLT, respectively (Fig. 2). Formetastatic carcinoid tumors, the survival rate was 80%,80%, and 69% at 1, 3, and 5 years, respectively. Formetastatic NCA, the survival rate was 38%, 15%, and8% at 1, 3, and 4 years, respectively. The longest survivalin the NCA group was 51 months after OLT. The differ-ence in overall (Fig. 1) and disease-free survival (Fig. 2)



between patients with carcinoid tumors and NCA was

highly significant (p < 0.001).

DISCUSSION

This multicentric study, including all OLT for meta-static NET performed in France between 1989 and 1994,is the largest reported series and is of epidemiologic valuegiven the rarity of this therapeutically challenging disease.Two disappointing findings were the low overall survivalat 5 years (36%) and low disease-free survival at 5 years

(17%). Interestingly, however, survival rates were sig-nificantly higher for carcinoids (69% at 5 years) thanNCA. Two explanations can be proposed for this differ-ence. The first is lower postoperative mortality in patientswith carcinoid tumors (7%), and the second is that recur-

rences of carcinoid tumors, albeit occurring at the same

rate as in the NCA group, were more compatible withlong-term survival. Three patients who presented carci-noid tumors in this series are living at 5 years after OLTdespite recurrence. In this regard, it should be emphasizedthat the median duration of pretransplant history of he-patic metastasis was not significantly different in the twogroups.

Our perusal of the literature (1989 to 1996) turned up

37 cases of OLT for metastatic NET with sufficient datafor analysis (Table 3). More than half of these cases in-volved symptomatic hormonal syndrome. Postoperativemortality in this compiled series was 1 % (4 of 37 cases).Eleven other patients died during follow-up, including 10from recurrence, with a median delay of 10 months afterOLT (range, 5 to 67). Twenty-three patients are still liv-

100

80-

~60-

6 40jln ~~~~~~L carcinoids: n= 154 -

200

non carcinoid apudomas : n = 16

0 20 40 60 80

months after transplantation

Figure 2. Disease-free survival after OLT for metastatic neuroendo-crne tumors. Carcinoids vs. noncarcinoid apudomas; p < 0.001.

ing, with a median follow-up of 16 months (range, 4 to106), including three presenting recurrence. Cumulativesurvival for these 37 patients was estimated by the KaplanMeier method based upon the duration of survival speci-fied for each patient in each report. Actuarial patient sur-vival was 66%, 56%, 46%, 46%, and 46% at 1-5 yearsafter OLT, respectively. These rates are slightly higherthan those reported in our series, but it should be notedthat follow-up was limited in the compiled series, withonly 5 of 37 patients still being at risk at 3 years. The 3-year survival rate was the same as in our series. In thecompiled series, there were 17 metastatic carcinoid tu-mors originating from the ileum in 6 cases, pancreas in3 cases, lung in 3 cases, stomach in 2 cases, duodenumin 1 case, anus in 1 case, and an undetermined locationin 1 case, and 20 NCA, including 14 pancreatic islet cellcarcinomas. Surprisingly, the survival rate was signifi-cantly higher for NCA than for carcinoids (83% at 2 yearsversus 34% at 2 years; log rank = 9.49, p < 0.01) dueto high postoperative mortality and recurrence rate in thecarcinoid group.The largest previously reported unicentric series were

the King's College series, the Hanover series, and thePittsburgh series. In the King's College series, which wasincluded in the compiled series,26 there were a total of 11cases, including 6 patients with carcinoids and 5 patientswith NCAs. Median survival after OLT was not signifi-cantly different in the carcinoid group and NCA group(20 months versus 18 months), but recurrence was ob-served in 5 of the 6 patients with carcinoids versus only1 of the 5 patients with NCAs. However, the fact thatmedian time from initial diagnosis to OLT was longer inthe carcinoid group than in the NCA group (71 monthsversus 16 months) raises the possibility that OLT wascarried out later in the course of the disease in the formerthan latter. The Hanover group reported 11 patients withOLT for metastatic NET, including 9 patients with carci-noids. Despite discouraging initial results'3, actuarial sur-vival was 81% at 1, 3, and 5 years.2 However, it shouldbe stressed that only three patients in this series had fol-low-ups of >3 years. In the Pittsburgh series, the bestresults after the cluster procedure were obtained in thesubgroup of 14 patients with NET. The number of carci-noids and NCAs was not mentioned. Survival was 64%at 1 and 3 years.27The 5-year survival rate after nontransplant treatment

of NET ranges from 25 to 35%.3411 However, this figurecannot be compared to the results of liver replacement,which is generally performed in symptomatic patientsonly after other therapies become ineffective. In our se-ries, 71% of patients were transplanted due to symptomsrelated to tumor bulk, hormone secretion, or both. Only16% had not undergone any medical or surgical treatmentprior to OLT. The 5-year survival after diagnosis of he-

Vol. 225 * No. 4


Table 3. SERIES OF ORTHOTOPIC LIVER TRANSPLANTATION FOR NEUROENDOCRINETUMORS COMPILED FROM THE LITERATURE (1989-1996)

Endocrine-Patient Sex, Related Follow-up

Reference (yr) Age (yr) Primary Tumor Type Location Symptoms Status (mo)

Ringe et al.13 (1989)

Makowka et al.15 (1989)

Mieles et al.16 (1990)

Olthoff et al.17 (1990)Bramley et al.18 (1990)Alsina et al.19 (1990)Schweizer et al.20 (1993)

Gulanikar et al.21 (1991)Lobe et al.22 (1992)Frilling et al.23 (1994)Curtiss et al.24 (1995)

Routley et al.26 (1995)Amold et al.14 (1989)

Anthuber et al.25 (1996)

F, 59F, 18F, 51M, 41F, 52F, 41M, 39M, 45F, 37M, 27F, 41

F, 41M, 51M, 47F, 46F, 55F, 11M, 52F, 40M, 52M, 565451465659504837435542

F, 34F, 62M, 52M, 57

CarcinoidGRFomaCarcinoidGlucagonomaCarcinoidGlucagonomaCarcinoid (+CCA)GastrinomaCarcinoidCarcinoidCarcinoidNeuroendocrineVIPomaGlucagonoma/carcinoidNonfunctioningNeuroendocrineCarcinoidInsulinomaCarcinoidNonfunctioningVIPomaNonfunctioningCarcinoidCarcinoidCarcinoidCarcinoidCarcinoidCarcinoidApudomaApudomaApudomaApudomaApudomaNonfunctioningGlucagonomaCarcinoidCarcinoid

IleumJejunumIleumPancreas?IleumPancreas*lleum*Pancreas*Duodenum*Stomach*Pancreas*Pancreas*Pancreas*Pancreas*Pancreas*

Stomach*Pancreas*LungPancreas*PancreasPancreas*AnusUnknownIleumIleumLungLungUnknownLungUnknownPancreasPancreasKidneyPancreas*Pancreas*Pancreas

Yes

YesNoNoYesYesYes

YesNoNoNoYesYesYesNoYesNoNoNoYesYesYesYesNoNoNoYesYesNo

DODAlive, NEDDied after operationAlive, NEDDied after operationAlive, NEDDOD (CCA)DODAlive, NEDDied after operationAlive, NEDAlive, NEDAlive, NEDAlive, recurrenceAlive, NEDAlive, NEDDODAlive, NEDAlive, NEDAlive, NEDAlive, NEDAlive, NEDAlive, recurrenceDODAlive, NEDDODDODDODAlive, recurrenceAlive, NEDAlive, NEDDied, NEDAlive, NEDDODDODDied after operationDOD

DOD = died of recurrent disease; NED = no evidence of disease; CCA = cholangiocarcinoma; GRF = growth hormone-releasing factor; VIP = vasoactive intestinalpolypeptide.* Primary tumor removed at the time of orthotopic liver transplantation.

patic metastasis in our OLT series was 57%. This com-

pares favorably with conventional treatment.Results ofOLT could be improved by reducing surgical

mortality and recurrence rate. In our series, the morbidityof upper abdominal exenteration was unacceptably high;four of seven patients who underwent this procedure diedof surgical complications, and the remaining three diedof severe physiologic disturbances related to total resec-

tion of the stomach and pancreas. Despite much greaterexperience in the Pittsburgh series, the mortality rate fromcauses other than tumor recurrence was still 28% after

cluster procedure.27 Based on these observations, it seemsadvisable to use a resection technique that preserves partof the stomach and/or pancreas: partial gastrectomy, distalpancreatectomy, or Whipple resection with or withoutanastomosis of the pancreatic remnant. When possible,these methods seem to be safer than composite liver-pancreas-duodenum graft, which led to fatal postoperativecomplications in all three cases in our series. Anotherway to improve postoperative recovery may be two-stagetreatment of the primary tumor and the hepatic metasta-sis.7'26'28 This strategy violates the rule that en bloc resec-

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tion should be performed for cancer patients but offersthe following three advantages: 1) thorough assessmentof lesions during the first procedure to rule out extrahe-patic tumor invasion; 2) sufficient time for medical treat-ment of liver metastasis and observation of metastaticevolution; and 3) lower risk of the transplantation proce-dure, especially in patients with pancreatic NET. How-ever, the risk of OLT after extensive dissection of theupper mesocolic region should not be underestimated.28To reduce the risk of recurrence after transplantation,

a thorough pretransplant evaluation is needed to excludethe presence of extrahepatic tumor deposits and thus en-sure that the OLT can eradicate the whole disease. Itshould be underlined that the next most frequent site ofdistant metastasis after the liver is bone.3 Several patientsin our series and in those reported previously''21'25'26 pre-sented early metastasis of the bone, which was often thefirst site of recurrence. In this regard, it should be notedthat somatostatin receptor scintigraphy appears highlysensitive for the detection of lung and bone metastasis ofNET.23'25'28'31'32

Whether all types of metastatic NET should be consid-ered for OLT remains controversial. Unlike the previouscases in the compiled series, our results indicate that OLTachieves better results for carcinoid tumors than for NCA.However, it should be noted that carcinoid tumors of thepancreas herald shorter survival than midgut or hindgutcarcinoids."'25 In this regard, it has stated that carcinoidtumor of the pancreas should be considered and managedas islet cell carcinoma producing serotonin.3 Some au-thors have suggested that early recurrences of carcinoidtumors after OLT could be due to a combination of immu-nosuppression and the presence of aneuploid cell lines inthe primary tumor.2' The second condition is probablyuncommon because most carcinoid tumors have a diploidDNA profile, indicative of low malignant potential,2"33but DNA analysis by flow cytometry could be useful forpatient selection.As regards the timing of transplantation in patients with

tumors of low malignant potential whose spontaneoussurvival can be long, we agree with previous au-thors6'7'24'25'26 that OLT may be indicated 1) for patientswith symptoms due to hepatomegaly or hormone produc-tion, 2) following resection of the primary tumor, and 3)after failure of other available treatments despite possiblerisks and side effects. Patients with carcinoid tumors ofthe lung and gastrointestinal tract who often fulfill thesecriteria could be an indication of choice. Our results sug-gest that OLT may not be indicated in other cases.

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results of liver transplantation in the treatment of metastatic

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