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Should we biopsy each liver mass suspicious for hepatocellular carcinoma before liver transplantation?–Yes

2005; Elsevier BV; Volume: 43; Issue: 4 Linguagem: Inglês

10.1016/j.jhep.2005.07.014

1600-0641

J. Wallis Marsh, Igor Dvorchik,

Liver Disease Diagnosis and Treatment

The treatment of patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) unfortunately cannot be based solely on oncologic principles but must encompass the allocation of a scarce resource—the donor liver. However, this confounding factor cannot be used to disregard the basic principles of oncology but the policy, instead, must combine these factors into an equitable distribution system for patients with HCC awaiting OLT. There are many publications which show that survival after transplant for HCC under the current Milan/UNOS criteria is excellent; some, in fact, report survival equal to that in patients without malignancy [1Gonzalez-Uriarte J. Valdivieso A. Gastaca M. Errasti G. Campo M. Hernandez M.J. et al.Liver transplantation for hepatocellular carcinoma in cirrhotic patients.Transpl Proc. 2003; 35: 1827-1829Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 2Khakhar A. Solano E. Stell D. Bloch M. Dale C. Burns P. et al.Survival after liver transplantation for hepatocellular carcinoma.Transpl Proc. 2003; 35: 2438-2441Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 3Regalia E. Coppa J. Pulvirenti A. Romito R. Schiavo M. Burgoa L. et al.Liver transplantation for small hepatocellular carcinoma in cirrhosis: analysis of our experience.Transpl Proc. 2001; 33: 1442-1444Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 4Adam R. Azoulay D. Castaing D. Eshkenazy R. Pascal G. Hashizume K. et al.Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy?.Ann Surg. 2003; 238: 508-518Crossref PubMed Scopus (270) Google Scholar, 5Bismuth H. Majno P.E. Adam R. Liver transplantation for hepatocellular carcinoma.Semin Liver Dis. 1999; 19: 311-322Crossref PubMed Scopus (400) Google Scholar, 6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (826) Google Scholar, 7Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1519) Google Scholar, 8Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5964) Google Scholar]. If this is the unified goal of the global transplant community then biopsy is certainly not required in every case being considered for transplantation, and the status quo can remain intact. However, if the objective is to identify and offer OLT to the approximately 35-40% of patients outside the current UNOS criteria who will not suffer HCC recurrence after OLT [[9]Marsh J.W. Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure?.Liver Transpl. 2003; 9: 693-696Crossref PubMed Scopus (117) Google Scholar], then the current staging systems which have been shown repeatedly to be inadequate for organ distribution must evolve [10Marsh J.W. Dvorchik I. Bonham C.A. Iwatsuki S. Is the pathologic TNM staging system for patients with hepatoma predictive of outcome?.Cancer. 2000; 88: 538-543Crossref PubMed Scopus (209) Google Scholar, 11Yao F.Y. Ferrell L. Bass N.M. Bacchetti P. Ascher N.L. Roberts J.P. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria.Liver Transpl. 2002; 8: 765-774Crossref PubMed Scopus (383) Google Scholar, 12Llovet J.M. Bruix J. Fuster J. Castells A. Garcia-Valdecasas J.C. Grande L. et al.Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power.Hepatology. 1998; 27: 1572-1577Crossref PubMed Scopus (372) Google Scholar].In the modern age of molecular biology, these are compelling reasons that liver transplantation for cancer must not rely solely on TNM-based systems which ignore the predictive power of such tools as DNA-based genotyping and microarrays. Patients with Stage II HCC in accordance with the modified Tumor-Node-Metastasis (TNM) Staging Classification (Table 1) may receive extra priority on the waiting list. The patient must have undergone a thorough assessment to evaluate the number and size of tumors and to rule out any extrahepatic spread and/or macrovascular involvement. A pre-listing biopsy is not mandatory, but the lesion must meet the following imaging criteria. The assessment of the patient should include ultrasound (US) of the patient's liver, a computerized tomography (CT) or magnetic resonance imaging (MRI) scan of the abdomen that documents the tumors and a CT of the chest that rules out metastatic disease. In addition, the patient must have at least one of the following: a vascular blush corresponding to the area of suspicion seen on the above imaging studies, an alpha-fetoprotein level of >200 ng/ml, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of the lesion, or radiofrequency ablation, cryoablation, or chemical ablation of the lesion. A patient not meeting the above criteria may continue to be considered a liver transplant candidate but must be listed at the calculated MELD/PELD score with no additional priority given because of the HCC diagnosis. All other patients with HCC including those with downsized tumors (i.e. having undergone ablative therapy) whose original/presenting tumor was greater than a Stage T2), must be referred to the applicable regional review board for prospective review [[13]Policy 3.6.4.4 on organ allocation from the UNOS website (www.unos.org).Google Scholar].Table 1American Liver Tumor Study Group Modified Tumor-Node-Metastasis (TNM) Staging ClassificationClassificationDefinitionTX, NX, MXNot assessedTO, NO, MONot foundT11 nodule <=1.9 cmT2One nodule 2.0-5.0 cm; two or three nodules, all 5.0 cm; two or three nodules, at least one >3.0 cmT4aFour or more nodules, any sizeT4bT2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or ultrasoundN1Regional (portal hepatis) nodes, involvedM1Metastatic disease, including extrahepatic portal or hepatic vein involvementStage 1T1Stage IIT2Stage IIIT3Stage IVA1T4aStage IVA2T4bStage IVBAny N1, any M1 Open table in a new tab As stated above, a patient with presumed Stage T2 HCC may receive upgrading on the UNOS waiting list equivalent to a MELD score of 22 (a 15% probability of candidate death within 3 months) based only on suspicion of HCC but without a biopsy. (The median waiting time for patients with this MELD score is 154 days.) Further, a patient whose initial status is >T2 may receive the additional listing points after having the tumor(s) downgraded by highly invasive procedures such as chemoembolization, radiofrequency ablation, cryoablation, or chemical ablation of the lesion, again all without a biopsy (i.e., no actual proof that the patient ever had HCC). A recent review of the UNOS database by Freeman described 400 cases with complete information for patients listed and subsequently transplanted with suspected HCC [[14]Freeman, RB personal communication. Abstract in press.Google Scholar]. Of these, 235 did not have a preoperative ablative procedure, meaning the explant specimen could be fully evaluated for confirmation of HCC. Surprisingly, 59 or 25% had no evidence of HCC on the explant pathology report. Of the 165 cases that did undergo a preoperative ablative procedure, only 66 (40%) had a preoperative biopsy reported in the UNOS database. The explant pathology showed that 104/165 (63%) had HCC detected. Thirty seven cases (22%) cases had only necrosis or infarct on histology, but 6 (16%) of these had had a positive biopsy prior to the ablation. (The remaining 24 cases had non-malignant diagnoses.) Therefore, only 110/165 (66%) of the ablated cases had documented proof of HCC. Obviously for a biopsy to become mandatory prior to OLT, the biopsy (1) must provide useful information not available through other means (e.g. radiological imaging±blood work) and (2) must not pose a significantly increased risk to the patient. It is difficult, if not impossible, to ascertain the true risk of percutaneous liver biopsy, and there is insufficient data to asses the risk through laparoscopy. There are 2 main potentially life-threatening risks involved with the biopsy of a mass(es) in a cirrhotic liver—bleeding and seeding of the biopsy tract with tumor cells. The risk of bleeding is rarely ever quoted as a reason not to perform the biopsy and should not exceed that of a biopsy of any cirrhotic liver, assuming the mass is not on the hepatic surface. Tumor tract seeding is, however, often quoted in the literature as a compelling reason not to biopsy suspicious hepatic masses since the diagnosis can often be established through other means (though the review of the UNOS database cited above raises serious doubts about this). This would be a logical argument if the establishment of the diagnosis of HCC alone were sufficient for distributing organs to those without other options for cure or long-term survival. Unfortunately, this is not the case. It is almost certain that the incidence of tumor-tract seeding is under-reported, especially in small centers with isolated cases; however, this does not mean that the percentage of tumor tract seeding would increase even if all cases were reported since the denominator (i.e. the total number of biopsies) would increase as well. The incidence of tumor tract seeding reported in the larger series ranges from 0.003 - 0.009% though an incidence as high as 1.9% has also been reported [15Smith E.H. Complications of percutaneous abdominal fine-needle biopsy.Rev Radiol. 1991; 178: 253-258PubMed Google Scholar, 16Schotman S.N. De Man R.A. Stoker J. Zondervan P.E. Ijzermans J.N. Subcutaneous seeding of hepatocellular carcinoma after percutaneous needle biopsy.Gut. 1999; 45: 626-627Crossref PubMed Scopus (43) Google Scholar, 17Huang G.T. Sheu J.C. Yang P.M. Lee H.S. Wang T.H. Chen D.S. Ultrasound-guided cutting biopsy for the diagnosis of hepatocellular carcinoma—a study based on 420 patients.J Hepatol. 1996; 25: 334-338Abstract Full Text PDF PubMed Scopus (135) Google Scholar]. Importantly, even when tumor tract seeding did occur, these authors concluded that the patients' outcome was ultimately not affected. While there is no doubt that tumor tract seeding does occur, it is also equally convincing that tumor tract seeding is rarely, if ever, tantamount to metastatic disease. Almost all cases of tumor tract seeding reported in the literature for patients undergoing OLT were cured by excision of the subcutaneous tumor deposit. It has been proposed that the need to biopsy small lesions suspicious for HCC should be mitigated by the lack of diagnostic accuracy of such lesions and by the fact that a majority of very small lesions are not ultimately proven to be HCC. A conference of the European Association for the Study of the Liver concluded that lesions less than 1 cm did not require immediate investigation but only an increase in ultrasound (US) surveillance. The rationale for this decision was based on the probability that these lesions are not malignant (∼50%) and that it is 'almost impossible to correctly diagnose it as such with the current diagnostic tools' [[18]Bruix J. Sherman M. Llovet J.M. Beaugrand M. Lencioni R. Burroughs A.K. et al.Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (3839) Google Scholar]. However, a prospective multi-center study on HCC screening involving more than 4000 newly-diagnosed cirrhotic patients in Italy over a 9 year period contradicts these arguments [[19]Caturelli E. Solmi L. Anti M. Fusilli S. Roselli P. Andriulli A. et al.Ultrasound guided fine needle biopsy of early hepatocellular carcinoma complicating liver cirrhosis: a multicentre study.Gut. 2004; 53: 1356-1362Crossref PubMed Scopus (121) Google Scholar]. During the study period, 688 new focal hepatic lesions were detected, 294 of which were 2 cm or less. Twenty of the lesions were immediately diagnosed as HCC based on serum AFP and had no further evaluation. The remaining 274 underwent ultrasound-guided FNB. Of these, 245 (89.4%) received pathologic diagnoses ultimately considered to be correct, 210 (85.7%) of which were HCC. When the lesions were divided by size, the FNB diagnostic accuracy was 88.6% for lesions ≤1 cm, 86.2% for lesions 1.1–1.5 cm, and 91.3% for lesions between 1.6 and 2.0 cm. When advancing the notion that a biopsy is not needed to establish the diagnosis of HCC prior to OLT, one must consider the consequences of a false-negative diagnosis of HCC: (1) patients who are awarded additional points on the waiting list and are ultimately proven not to have HCC may be transplanted prematurely, and (2) a certain percentage of patients who are bypassed by these patients will die having never received the benefit of OLT. This being said, it is certainly conceded that not all attempts at biopsy of suspicious lesions will yield a positive diagnosis, even when HCC is actually present; however, as shown in the Italian study cited above, the biopsy risk even for the smallest detectable lesions is considerably less than the risk of being transplanted without HCC when the diagnosis is made without a biopsy. Certainly no other circumstance comes to mind when a patient with a lesion suspicious for cancer which could be biopsied is simply watched for tumor progression without treatment based on the probability that such a small lesion is unlikely to be carcinoma. No one would argue that treating cancer at a later stage is ever preferable to treating cancer at an earlier stage; however, this is the algorithm which our current system mandates. In fact, it is this algorithm (transplanting such a relatively high percentage of patients for suspected HCC who ultimately were proven not to have carcinoma at transplant) which resulted in the removal of the extra listing points for patients with Stage T1 HCC. In addition to a true diagnosis, there is a wealth of predictive molecular information which can be gained from the preoperative biopsy of an HCC. As we have previously described, a positive biopsy can yield valuable predictive information such as the fractional allelic loss rate (FAL) of a panel of nine microsatellites (Table 2) [20Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (125) Google Scholar, 21Finkelstein S.D. Marsh W. Demetris A.J. Swalsky P.A. Sasatomi E. Bonham A. Subotin M. et al.Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma.Hepatology. 2003; 37: 871-879Crossref PubMed Scopus (94) Google Scholar]. (The FAL is calculated by dividing the number of mutated microsatellites by the total number of microsatellites for which the patient was found to be informative.) The predictive power of FAL surpasses even that of vascular invasion.Table 2Microsatellites and their associated genes used to calculate the FAL rateMicrosatelliteAssociated Gene17p13 D17S 974TP5317p13 D17S 1289TP5318q21 D18S 814DCC1p34D1S407p343p26 D3S 1539OGG15q21 D5S 615APC9p21 D9S 251CDKN2A1p34 MYCL 5NTMYC117p13 TP53 I1TP53 Open table in a new tab We recently reviewed 171 patients transplanted in the presence of HCC for whom we had FAL information; all patients had at least 5 years of follow-up. Forty-six cases with macrovascular invasion, positive lymph nodes, positive margins or metastatic disease were excluded from review because of the almost uniform disease recurrence and because these patients would be excluded by the current UNOS criteria. Of the remaining 125 cases, 75 were inside the UNOS/Milan criteria. The mean survival for this group was 15.1 years. The mean tumor-free survival for those outside the UNOS criteria was 9.7 years. (Fig. 1) Four patients (5.3%) inside the UNOS criteria suffered tumor recurrence; 21/50 (42%) of the patients outside the UNOS criteria suffered cancer recurrence while 29/50 (58%) did not. While a 94.7% non-recurrence rate (those inside the UNOS criteria) is excellent, it is perhaps too excellent as it denies consideration for OLT to the 58% of patients outside the criteria who also would not suffer tumor recurrence. In an effort to gain insight into the potential usefulness of the molecular information that can be provided by biopsy, we stratified all 125 patients only by the fractional allelic loss rate (FAL), ignoring all other components of the current listing criteria. The patients were divided into 3 groups: Group 1—those 78 patients with an FAL≤20%; Group 2—those 24 patients with an FAL between 21 to 40%; Group 3—those 23 patients with an FAL > 40%. The means of tumor-free survival were 15.2 years, 8.5 years, and 3.7 years for groups 1, 2, and 3, respectively. (Fig. 2) The overall rates of non-recurrence were 93.59% (73/78), 70.83% (17/24), and 43.48% (10/23) for groups 1, 2, and 3, respectively (P<0.0001). Therefore, the measurement of FAL alone would allow 27 (21.6%) additional patients to receive LT, assuming of course that the mean tumor-free survival rate of 8.5 years and a recurrence rate of 29.2% (those in Group 2) would be acceptable to the transplant community, which is well within the suggested 50% 5-year survival rate suggested in a recent review by Llovet, et al. [[22]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3858) Google Scholar]. The same analysis was performed on those 75 patients inside the UNOS/Milan criteria. There were 60 patients in Group 1, 11 patients in Group 2, and 4 patients in Group 3. The means of tumor-free survival were 15.5 years, 8.1 years, and 4.4 years for groups 1, 2, and 3, respectively (P<0.03). The rates of non-recurrence were 96.67% (58/60), 90.91% (1/11), and 75% (1/4) for groups 1, 2, and 3, respectively. (Fig. 3) The use of FAL could have excluded at least 3 patients inside the UNOS criteria (Group 3) who would have suffered recurrence. While 1 patient in group 3 who did not suffer recurrence would have been excluded from OLT, this is considerably less than the 29 patients outside the current criteria who would not suffer the recurrence. Finally, the analysis was also performed on those 50 patients outside the UNOS/Milan criteria. There were 18 patients in Group 1, 13 patients in Group 2, and 19 patients in Group 3. The mean tumor-free survival rates were 13.8 years, 7.4 years, and 3.5 years for groups 1, 2, and 3, respectively (P<0.0001). The rates of non-recurrence were 83.33% (15/18), 53.85% (7/13), and 36.84% (7/19) for groups 1, 2, and 3, respectively. (Fig. 4). Once again, depending upon the philosophy of the transplant community for an acceptable recurrence rate, 31 patients (Groups 1 and 2) who are currently being excluded from receiving additional listing could have been offered OLT if molecular tools currently available were incorporated into listing criteria. This would, of course, require a biopsy. In conclusion, as shown in Table 3, there are compelling reasons to biopsy every lesion suspicious for HCC in patients being considered for transplantation. At an absolute minimum, patients with Stage T1 HCC should have the option of undergoing a biopsy which, if positive for HCC when also combined with a low FAL rate, should enable that patient to be upgraded on the waiting list. There is never a time which could be considered too premature to treat cancer.Table 3Summary of reasons to biopsy lesions suspicious for HCC prior to OLT1To establish a diagnosis2To enable the awarding of extra listing points only to those who truly have HCC3To decrease the incidence of transplanting patients prematurely who do not have HCC4To enable those patients without HCC to receive a transplant without risk of being surpassed by patients with a false-negative diagnosis based on imaging and blood work5To move beyond the current staging systems into a more equitable organ allocation policy. Open table in a new tab