High Pathological Risk of Recurrence After Surgical Resection for HCC

8/17/2019 High Pathological Risk of Recurrence After Surgical Resection for HCC

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High Pathological Risk of Recurrence After SurgicalResection for Hepatocellular Carcinoma: An Indication

for Salvage Liver Transplantation

Margarita Sala,

1

Josep Fuster,

2

Josep M. Llovet,

1

Miquel Navasa,

1

Manel Sole ´,

3

Marı́a Varela,1 Fernando Pons,1 Antoni Rimola,1 Juan Carlos Garcı́a-Valdecasas, 2

Concepció Brú,4 and Jordi Bruix 1 for the Barcelona Clı́nic Liver Cancer (BCLC) Group

Surgical resection and liver transplantation offer a 5-yearsurvival greater than 70% in patients with hepatocellularcarcinoma, but the high recurrence rate impairs long-termoutcome after resection. Pathological data such as vascu-lar invasion and detection of additional nodules predict recurrence and divide patients into high and low risk profile. Based on this, we proposed salvage liver transplant to resected patients in whom pathology evidenced high

recurrence risk even in the absence of proven residualdisease. From January 1995 to August 2003 we have eval-uated 1,638 patients. Resection was indicated in 77patients, but only 17 (22%) (all cirrhotics, 14 hepatitis C virus) were optimal candidates for both resection andtransplantation. Of them, 8 exhibiteda high risk profileat pathology and were offered transplantation. Among the 8high risk patients, 7 presented recurrence, compared withonly2 ofthe 9 at lowrisk (P .012). Two of the high risk patients refused transplant and developed multifocal dis-ease during follow-up. The other 6 were enlisted and allbut 1 had tumor foci in the explant. Only 1 presentedextrahepatic dissemination early after transplant and died4 months later. The others are free of disease after a median follow-up of 45 months. Two recurrences were

detected in lowrisk patients, 1 of them being transplanted18 months after surgery. These data in a small series of patients confirm that pathological parameters identify patients at higher risk of recurrence, which allow them to

be listed for liver transplantation without proven malig-nant disease. In conclusion, this policy is clinically effec-tive and could further improve the outcome of resectedpatients. (Liver Transpl 2004;10:1294–1300.)

H epatocellular carcinoma (HCC) is the 5th mostcommon cancer worldwide and the 3rd mostcommon cause of cancer-related death.1 Radical treat-ments for early hepatocellular carcinoma are surgicalresection, liver transplantation (LT), and percutaneoustreatments.2 However, there are no randomized controltrials (RCTs) comparing these treatments, and the bestoption depends on the results obtained in observationalstudies. LT is the best option in patients with decom-pensated cirrhosis and single HCC 5 cm or showing up to 3 nodules, each of them 3 cm. However, thereis a major controversy in cirrhotic patients with pre-served liver function and solitary tumors. Survival aftersurgical resection in Child Pugh A patients withoutsignificant portal hypertension and normal bilirubin issimilar to that obtained with LT,3 and the main differ-ence lies in the higher tumor recurrence rate after resec-tion—above 70% at 5 years vs. 15% after LT.3–5 This isthe major argument used by some authors to supportLT as the first treatment option.

Several studies have shown that the risk of recur-rence might be predicted by the presence of microvas-cular invasion or additional nodules.3,6–10 and, there-fore, both parameters could be used to divide already resected patients into those with low recurrence risk andthose with high risk. Interestingly, the recurrence rate intransplanted patients who present a high risk profile in

the explanted liver is slightly increased. However, it isnot prohibitive,3,4,11,12 and this suggests that this sub-group of patients would have been better served by transplantation.

In our Unit, surgical resection is the first optionoffered to HCC patients without significant portalhypertension and normal bilirubin. Following theabove reasoning, we proposed in 1995 that it could be

worthwhile to propose enlisting for LT to those patients

Abbreviations: HCC, hepatocellular carcinoma; LT, liver trans-

plantation.From the 1Liver Unit, 2 Surgery Department, 3Pathology Depart -

ment, and 4 Radiology Department, Institut d’Investigacions Bio-

me `diques August Pi i Sunyer (IDIBAPS), Hospital Clı́nic, University of

Barcelona, Catalonia, Spain.Supported by a grant from Instituto de Salud Carlos III (grant

number C03/02); a contract from Programa “Ramon y Cajal”

(IDIBAPS, Ministerio de Ciencia y Tecnologı́a) (to J.M.L.); and a

research grant from the Hospital Clı́nic of Barcelona (to M.V. and M.Sala); a grant from de Instituto de Salud Carlos III (Ministerio de

Sanidad y Consumo) (to M. Sala). Address reprint requests to Jordi Bruix, BCLC Group, Liver Unit,

Hospital Clı́nic i Provincial, Villarroel 170, 08036-Barcelona, Catalo-

nia, Spain. Telephone: 34-3-2279803; FAX: 34-93-2275792; E-mail:[email protected]

Copyright © 2004 by the American Association for the Study of

Liver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20202

1294 Liver Transplantation, Vol 10, No 10 (October), 2004: pp 1294 – 1300


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with solitary HCC who were treated by surgical resec-tion and in whom the pathological assessment evi-denced parameters of a high risk of recurrence. Thisnovel policy differs from that applied by most of thegroups who follow resected patients and consider sal-

vage transplantation upon detection of recurrence.13–19

The present study describes the results we haveobtained with this strategy.

Patients and Methods

Between January 1995 and August 2003, 1,638 patients withHCC were diagnosed, staged, and treated in our Liver Unitfollowing a previously published schedule.20 Cirrhoticpatients with early HCC (single tumors 5 cm or 3 nod-ules 3 cm each) are considered for radical therapies. Resec-tion is indicated for patients with single tumors, absence of significant portal hypertension, and normal bilirubin.Patients with significant portal hypertension, abnormal bili-rubin, or 3 nodules 3 cm are considered for LT (if youngerthan 65 years old and without severe associated diseases).Percutaneous treatments are applied when surgery is pre-cluded. For patients in an intermediate stage, the first optionis arterial chemoembolization, and those diagnosed at anadvanced stage are considered for phase II-IV trials. Finally,end stage patients (Okuda III,21 Performance status 3-422)receive symptomatic treatment.

During this period of time, 77 cirrhotic patients withHCC were suitable for surgical resection, but only 17 (22%) were optimal candidates for both resection (first option) andLT ( 65 years old without severe associated conditions).

These patients were offered resection as a first option andconstitute the population of this cohort analysis to assess theefficacy of the above mentioned salvage strategy.

Sixteen patients were male, mean age was 55 7 years,and the etiology of underlying cirrhosis was hepatitis C virusin 14 cases. All patients had a preserved liver function (allbelonged to Child Pugh A group) anddid not have significantportal hypertension. According to preoperative staging, allhad single tumors that in 9 patients were 30 mm and in 8ranged between 30 and 50 mm. The mean tumor size was30 9 mm (range 15–50 mm) (Table 1).

Diagnosis of HCC was performed by needle biopsy in 12cases and by noninvasive criteria in 5 cases (2 coincidentalimaging techniques or 1 imaging technique with increased

alpha-fetoprotein). Preoperative staging included abdominalultrasound, dynamic computed tomography, and/or mag-netic resonance imaging. Additionally, a preoperative hemo-dynamic study with measurement of hepatic venous pressuregradient was also performed in order to exclude patients withsignificant portal hypertension (hepatic venous pressure gra-dient 10 mmHg).

Surgical technique included intraoperative ultrasound toexclude additional nodules, localize the tumor, and performan anatomical resection.

Resected liver specimens were serially sliced in .5 cm thick slices and fixed in formalin. Representative samples of tumor,nontumoral tissue, and surgical margins were embedded inparaffin for microscopic examination. Tumor number andsize were confirmed on gross inspection, and microscopic

analysis determined the presence of vascular invasion, micro-scopic tumor satellites, tumor differentiation, and status of the resection margin.

According to the pathological criteria, the patients weredivided into 2 groups: patients with high risk of recurrence if they had microvascular invasion and/or additional nodules orsatellites and patients with low risk of recurrence if they didnot have any of these parameters (Table 1). Patients of thehigh risk group were offered enlistment for liver transplanta-tion even in the absence of tumoral disease and followed every 3 months after enlistment by means of clinical examination,alpha-fetoprotein, abdominal ultrasound and computedtomography scan. Patients of the low risk group were advisedto attend regular follow-up every 6 months. Additional diag-

nostic techniques were performed upon suspicion of recur-rence to confirm malignancy, stage the disease, and indicatetreatment, which is based on the same strategy as depicted forthe primary tumor.

Statistical Analysis

Baseline characteristics of the patients are expressed asmean SD. Comparison between groups was done by using the Student’s t -test for quantitative variables, and the 2 testor the Fisher test for qualitative variables. Follow-up length isexpressed as median (range). Follow-up was computed asstarting from the resection date for all patients and was main-tained until death or last visit before December 15, 2003.

The calculations were done by the SPSS package (SPSS10.0, 1989– 1995, Chicago, IL).

Results

According to the pathological study of the resectedspecimen, patients were divided into 2 groups: patients

with high risk of recurrence (n 8) if they had addi-tional nodules and/or microvascular invasion andpatients with low risk of recurrence when these 2parameters were absent (n 9) (Fig. 1). The character-istics of both groups are depicted in Table 1. The resec-

tion border was tumor-free in all cases.

High Risk Patients

Amongst the 8 patients with high risk of recurrence, 6patients accepted to be enlisted for LT and 2 refused. Of the 6 patients enlisted, 2 developed tumor recurrence

while waiting. One patient presented a single tumor at12 months, and percutaneous ethanol injection was

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applied as adjuvant treatment. This patient was trans-planted 4 months after. The other patient developedmultifocal tumor recurrence 6 months after resectionand is currently still waiting for LT. The resected spec-imen of this patient showed a single HCC 40 mm insize, with microvascular invasion and without addi-tional nodules. Recurrence was not suspected prior toLT in the other 4 patients enlisted because of risk (median time from resection to LT: 12 months, range9–19). Median time elapsed between imaging studies

and LT was 53 days (range 14 – 93).Characteristics of the explanted liver in the 5 high risk

patients that have been transplanted are depicted in Table2. Only 1 patient had no tumoral recurrence in theexplanted liver. This patient was transplanted 9 monthsafter resection and presented both adverse pathologicalfindings. Theremaining 4 patientspresented tumor recur-rence. The patient whose tumor recurrence wastreated by percutaneous ethanol injection showed viable tumor in

the treated foci and 1 additional tumor nest. The other 3patients were transplanted without any evidence of tumorrecurrence, but the explanted liver showed recurrenttumor foci less than 2 cm, associated with microvascularinvasion in 2 patients.

At the end of follow-up (median follow-up 26months, range 4–84), 2 of the transplanted patientshad died. One patient (the 1 without tumor nests in theexplanted liver) died 7 years after LT because of recur-rent hepatitis C virus cirrhosis without HCC recur-

rence. The other patient, whose explanted liver showedmultiple foci of HCC and microvascular invasion, died4 months after LT due to peritoneal dissemination of HCC and intrahepatic spread.

Finally, the 2 patients whorefused enlistment for LTdeveloped a large multinodular recurrence not amena-ble for radical therapies at 4.5 and 50 months, respec-tively. They died at 10 and 18 months after recurrencedue to tumor progression.

Table 1. Characteristics of the Patients

Variables Overall (n 17) Low Risk (n 9) High Risk (n 8) P

Age (years) 55 7 54 8.5 56 5 ns

Gender (M/F) 16/1 8/1 8/0 nsEtiology of cirrhosis ns

HCV 14 6 8

HBV 1 1 —

Alcohol 1 1 —Other 1 1 —

AFP (ng/mL;10/11 100/101 400/400) 10 / 1 / 5 / 1 6 / 1 / 2 / 0 4 / 0 / 3 / 1 ns

Bilirubin (mg/dL) .9 .1 .9 .1 .8 .1 ns

Prothrombin activity (%) 88 10 89 11 88 10 ns Albumin (g/dL) 43 4 43 3 43 4 ns

AST (IU/L) 67 40 73 51 61 24 ns

ALT (IU/L) 100 65 107 84 92 36 nsHVPG (mmHg) 6.3 2.5 5.5 2.5 7.5 2 ns

Mean tumor size (mm) 30 9 29 12 30 6 ns30 mm 9 5 4

31– 50 mm 8 4 4Pathologic characteristics

Mean tumor size (mm) 32 13 29 13 35 12 nsDifferentiation degree ns

Well 6 5 1

Moderate 10 4 6

Poor 1 — 1Microvascular invasion As per design

Yes 7 / 10 — 7

No 10 9 1 Additional nodules As per design

Yes 3 — 3

No 14 9 5

Abbreviations: HCV, hepatitis C virus; HBV, hepatitis B virus; AFP, alpha-fetoprotein; AST, aspartate aminotransferase; ALT, alanineaminotransferase; HVPG, hepatic venous pressure gradient; ns, not statistically significant.

NOTE: Numbers expressed as mean standard deviation.

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Low Risk Patients

According to our strategy, these 9 patients were notoffered to be enlisted for LT after resection because of their low recurrence risk. However, 2 of them hadrecurrence during follow-up. One patient, initially hav-ing a solitary HCC of 4 cm encapsulated and welldifferentiated, developed a multinodular HCC 19

months after resection and was treated by transarterialchemoembolization. He is alive 55 months after resec-

tion. The 2nd patient, operated on because of a solitary

HCC of 2 cm without capsule and moderately differ-entiated, developed a solitary tumor recurrence and wasenlisted 18 months after resection. LT was performed 9months later and he is alive and free of recurrence 28months after LT (55 months after resection).

The remaining 7 patients are alive and without

HCC recurrence with a median follow-up of 55months (range 19– 103).

Figure 1. Results of the proposed decision policy for HCC patients treated by surgical resection after stratifying themaccording to the risk of recurrence based on pathology. TACE, transarterial chemoembolization; PEI, percutaneousethanol injection; mo, months.

Table 2. Characteristics of the High Risk Transplanted Patients

No.

Patient

Resected HCC

Time

(months)*

Explanted Liver

Recurrence†

Follow-Up

(months)‡

Size

(mm)

Vascular

Invasion

Additional

Nodules Tumor

Size

(mm)

Vascular

Invasion

Additional

Nodules

1 30 Yes No 19 Yes 5 Micro Yes Yes 4§2 40 Yes No 12 Yes 12 Micro No No 65

3 35 No Yes 9 Yes 9 Micro No No 26

4 25 Yes Yes 16 Yes 18 No Yes No 18

5 20 Yes Yes 9 No — — — No 84¶

Abbreviations: HCC: hepatocellular carcinoma.*Time from resection to liver transplantation.†Recurrence after liver transplantation.‡Time from liver transplant to the end of follow-up.§Patient with tumor recurrence after liver transplantation who died 4 months after.Patient treated percutaneously before liver transplantation.¶Patient with high risk of recurrence in whom explanted liver did not show tumor recurrence. This patient died 84 months after livertransplantation due to recurrent HCV cirrhosis.NOTE: The sixth patient is still awaiting liver transplantation.



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Discussion

Tumor recurrence is the major drawback after surgicalresection of HCC, and this is used by some authors tosupport LT as the first therapeutic option for these

patients.19,23,24

However, transplantation applicability and outcomes are curtailed by the shortage of donors.This creates a waiting time during which the HCC may progress and, when analyzed according to intention totreat the survival of the patients, might be less than thatoffered by surgical resection.3,25,26 Because of this, mostof the groups consider resection as the first treatmentapproach for patients who would be candidates for bothresection and LT.13–18,20 In such a scenario, the mainissue is how tomanage the riskof recurrence and to treatits development. Despite some encouraging results withInterferon,27 acyclic retinoids,28 radiation,29 and adop-tive immunotherapy,30 there is no effective therapy to

prevent tumor relapse.31 Thus, in the majority of cen-ters the established clinical practice is to carefully follow the resected patients and, upon detection of recurrence,consider the potential indication of so-called salvageLT.15 This approach has been heavily criticized foryears because initial studies suggested that LT afterresection would offer poorer results,19 but the data recently published by Belghiti et al.13 indicate that thesurvival after salvage LT is not significantly lower. Theexplanation for this discrepancy might be related to thebiological selection process that the patients haveundergone until reaching LT. This does not refer to a better identification of candidates by imaging tech-niques in order to exclude desperate patients withextensive multifocal recurrence, but to the fact that only those patients with a less aggressive recurrence wouldbecome candidates for salvage LT. It is well known thatthere are 2 major pathways leading to recurrence: tumordissemination prior to operation and de novo tumordevelopment in an oncogenic cirrhotic liver.32–40

In most cases, recurrence will be related to the firstmechanism (dissemination) and will very likely appearearly during follow-up as a multifocal involve-ment.32,39,41–43 This dissemination nature of recur-rence and its faster progression mean that patients will

not be candidates for salvage surgery. In fact, if enlistedupon detection of recurrence, they will experience a higher rate of exclusion while waiting, and even if they do reach transplantation, their outcome will be dismal.

By contrast, those infrequent patients in whom dis-semination has not taken place will most likely developsolitary de novo tumors and in that way become candi-dates for successful salvage therapy. While the retro-spective analysis of the database by Poon et al. suggests

that the majority of patients with recurrence couldbecome candidates for salvage LT, this is not supportedat all by the few available data in clinical prac-tice3,13,14,16,18,19,44 and even by theirown previous pub-lications.39,45 As a whole, less than 20% of the patients

are candidates for salvage surgery,46–56 and this low applicability was the major criticism of the Markov analysis on salvage LT performed by Majno et al. whoconsidered an 80% applicability rate upon recurrencedetection.15

According to all these comments, it is clear that thepolicy to wait for recurrence to develop and then indi-cate treatment is less than optimal. The risk of recur-rence can be accurately predicted by pathologic exami-nation of the resected tissue. Microvascular invasionand presence of satellites or additional intrahepatic neo-plastic sites are thought to be related to unrecognizedtumor spread prior to resection, and interestingly, thosetransplanted patients in whom pathology examinationdepicts these pathologic high risk parameters do notpresent a prohibitive rate of disease recurrence during follow-up.11,12 Therefore, for these patients LT shouldbe considered the best primary treatment.

Following this reasoning, we proposed a more activeattitude offering enlistment for LT to those patients

who after initial HCC resection would prove to bearthis pathologic high risk profile. The results of thisstudy demonstrate the efficacy of this novel policy.During the period of the investigation, we operated on77 patients and 17 of them qualified as candidates both

for resection and LT. According to our treatment strat-egy, they were offered resection as primary treatment,and based on the pathologic findings, 8 patients wereclassified athigh riskand9 atlow risk. All but 1 ofthoseat high risk showed recurrence either prior to LT (n2) or in the explanted liver in the absence of disease onimaging techniques (n 3). Unfortunately, 2 patientsdid not accept to be enlisted, and when recurrence wasdetected, it was recognized as multifocal and LT couldnotbe indicated as a salvage procedure. These 2 subjectssupport the aforementioned concept suggesting thatrecurrence due to dissemination is very unlikely to bedetected at a stage when salvage LT might be feasible. In

addition, we have also evidenced that this policy offersan adequate long-term outcome. Only 1 patient devel-oped massive or extensive tumor dissemination after LTand died 4 months after the operation. The other 4patients have been followed for a median of 45 monthsand show no tumor recurrence, there being only 1death at 84 months because of recurrent hepatitis Cvirus cirrhosis.

On the other hand, the outcome of patients classi-

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fied as low risk has also been encouraging. Only 2 out of the 9 patients in this group have recurrence. One of them was amenable to be enlisted for LT (successfully performed after 9 months waiting time), while theother was discarded due to multifocal disease and was

treated by transarterial chemoembolization. Theremaining 7 patients are all alive and free of disease aftera median follow-up of 55 months. They may developrecurrence during follow-up, but this will very likely bethe result of a de novo tumor in the cirrhotic liver.

Accordingly, this group of patients will benefit from a conservative approach with regular surveillance thatallows them to skip or delay the risks associated to LT.If HCC occurs, they will become optimal candidatesfor salvage LT.

It could be argued that the number of patients in which the need of LT is avoided is very limited, andtherefore, it makes no sense to maintain resection as thefirst option. However, any effort to optimize the use of the limited pool of cadaveric donors is worth undertak-ing.

In the future, the availability of effective adjuvanttherapies may effectively prevent recurrence, and/ormolecular profiling 57 will refine the risk assessmenteven prior to tumor resection. While these advance-ments take place, our active salvage transplantation pol-icy according to risk appears to be an effective treatmentpolicy for patients with surgical HCC. Obviously, con-firmation of our data by other groups should be avail-able prior to unequivocally recommending this policy

in conventional clinical practice.

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High Pathological Risk of Recurrence After Surgical Resection for HCC