Comparison of Liver Biopsy and Noninvasive Methods for Diagnosis of Hepatocellular Carcinoma

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:361–368

Comparison of Liver Biopsy and Noninvasive Methods for Diagnosis of Hepatocellular Carcinoma ELDAD S. BIALECKI,*,储 AMOBI M. EZENEKWE,‡,储 ELIZABETH M. BRUNT,‡,储 BRIAN T. COLLINS,‡,储 T. BRENT PONDER,‡,储 B. KIRKE BIENEMAN,§,储 and ADRIAN M. DI BISCEGLIE*,储 Departments of *Internal Medicine, ‡Pathology, and §Radiology, and the 储Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, Missouri

See CME exam on page 250 and editorial on page 296. Background & Aims: Current management guidelines for hepatocellular carcinoma (HCC) do not require biopsy to prove the diagnosis. We evaluated our experience of patients with liver disease and hepatic lesions suspicious for HCC who underwent both fine-needle aspiration and core biopsy and correlated the results with those from commonly used noninvasive approaches. Methods: We retrospectively reviewed the outcomes of a series of patients undergoing biopsy because of a suspicion of HCC and compared sensitivity, specificity, and predictive value of biopsy with existing noninvasive methods for diagnosing HCC. Results: HCC was diagnosed by biopsy in 74 (63%) of 118 cases, and an additional 10 were found to have HCC on follow-up. Patients with positive biopsy results had significantly higher serum ␣-fetoprotein levels (median, 57 vs 12; P ⴝ .014) than those with negative biopsies, although these 2 groups were otherwise similar with regard to tests of liver function, lesion size on imaging, and ChildPugh class. No patient developed evidence of tumor spread along the needle track after biopsy. We compared the diagnosis of HCC by biopsy with noninvasive diagnostic criteria advocated by the European Association for the Study of the Liver and those used by the United Network for Organ Sharing. Compared with criteria of the European Association for the Study of the Liver and the United Network for Organ Sharing, biopsy had greater sensitivity, specificity, and predictive value. Conclusions: We recommend a greater role for imageguided biopsy of lesions greater than 1 cm clinically suspicious for HCC to allow adequate treatment planning because the risks of biopsy appear small and the potential benefits significant. Obtaining material for both cytologic and histologic examination at biopsy maximizes the diagnostic yield.

epatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for approximately 1 million deaths annually.1 Although the

H

United States is considered a region of lower incidence, the number of HCC cases in this country has more than doubled during the past 3 decades, and more frequent screening of high-risk individuals has contributed to the detection of HCC earlier than in previous years.2 Clinical evaluation for HCC generally involves the measurement of serum tumor ␣-fetoprotein (AFP) levels and the use of imaging techniques such as ultrasound, multiphasic computed tomography (CT) scan, magnetic resonance imaging (MRI), or angiography. The role of liver biopsy in confirming clinically apparent HCC has been controversial, in large part because of the concern for tumor seeding.3 Since the implementation of the Model of End-stage Liver Disease (MELD) organ allocation system for liver transplantation in the United States in 2002, patients with HCC have received extra priority on the waiting list of the United Network for Organ Sharing (UNOS) and thus have increasingly undergone transplantation. The rate of false-positive diagnosis of HCC at time of transplant, however, was reported to be as high as 33% under the original version of the MELD system.4 Accurate diagnosis and staging of HCC are becoming ever more critical, particularly as more invasive therapeutic options have become available. It would appear that liver biopsy evaluation can provide a definitive diagnosis and thereby limit potentially unnecessary intervention,5,6 although this practice carries a small risk of spread along the needle track and a small risk of obtaining false-negative results. The indications and techniques for biopsying suspected HCC are not standardized, and the value of this approach is uncertain. We therefore set out to review our Abbreviations used in this paper: AFP, ␣-fetoprotein; CT, computed tomography; EASL, European Association for the Study of Liver Disease; FNA, fine-needle aspiration; HCC, hepatocellular carcinoma; MELD, Model for End-stage Liver Disease; MRI, magnetic resonance imaging; UNOS, United Network for Organ Sharing. © 2006 by the American Gastroenterological Association Institute 1542-3565/06/$32.00 PII: 10.1053/S1542-3565(05)00977-8

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experience at an academic medical center with a large number of patients with chronic liver disease where it is our practice to obtain biopsies of all hepatic lesions suspicious for HCC. This analysis integrates results of liver biopsy with other routine diagnostic and clinical tools and compares them to widely used noninvasive diagnostic criteria (eg, UNOS) to gain a better understanding of the diagnostic potential of these tests and thereby contribute to effective management of HCC.

Patients and Methods Patients All liver biopsies performed at Saint Louis University Hospital between January 1998 and July 2003 were identified from the Department of Pathology archives. From these, we identified all cases referred for biopsy of a hepatic lesion suspicious for HCC for which both fine-needle aspiration (FNA) and core biopsy were performed contemporaneously. Lesions were considered suspicious for HCC if the radiologist raised the issue of HCC in their report of the relevant imaging study. We reviewed the records of these patients by using all available computer and paper records from inpatient and outpatient visits. Data for analysis were abstracted from these records on the basis of the recommendations of the European Association for the Study of Liver Disease (EASL) Conference in 2000, which prescribed data to be included in studies dealing with HCC patients.7 Thus, patient demographics and liver function studies were recorded, as were tumor description assessed by ultrasound, CT scan, or MRI imaging modalities (including tumor size, number of nodules, and evidence of vascular invasion or metastasis). We used data from imaging studies done within 3 months before the date of the corresponding liver biopsy. Unless an exact size measurement was given, tumors described as small, discrete, ill-defined, irregular, or subtle were considered to be ⬍1 cm in diameter, and tumors described as large, diffuse, infiltrating, or heterogeneous in the absence of an exact size measurement were classified as ⬎5 cm. Laboratory values of serum AFP and tests for hepatic function were recorded on each patient at the time closest to the biopsy and no more than 3 months before. Ascites was documented either by results of abdominal imaging or by clinical findings together with the use of spironolactone. The presence of hepatic encephalopathy was noted on the basis of clinical findings together with the use of lactulose. Among patients with cirrhosis, the degree of hepatic dysfunction was estimated by using the Child-Pugh classification based on standard criteria.8 Assessment of general health measures such as performance status, pain, and “constitutional syndrome”9 was omitted as a result of the difficulties assessing these factors in a retrospective analysis. The details of this study were approved by the Saint Louis University Institutional Review Board.

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Biopsy Technique The histologic diagnoses of all patients were determined on the basis of results of the initial liver biopsy. Similarly, these initial results were used for calculation of sensitivity, specificity, and predictive value. If any subsequent biopsy material became available (including explant), this was used as follow-up information in determining whether HCC was present. The biopsy technique used a 17-gauge to 19gauge coaxial cannula positioned within the suspicious lesion under CT or ultrasound guidance. Thereafter, FNAs were performed, and material was obtained for immediate preliminary cytopathologic evaluation and diagnosis. Two or more direct smears of the aspirates were prepared and stained by using the Diff-Quick method. Repeat needle aspirates were requested by an onsite cytopathologist if insufficient samples were obtained. A provisional diagnosis was then issued, and a core biopsy needle was introduced via the same coaxial cannula. Between 2 and 5 cores of tissue were typically obtained. Core biopsies were fixed in 10% neutral buffered formalin and processed routinely (paraffin-embedded), and sections were stained routinely with hematoxylin-eosin, Masson’s trichrome, reticulin, iron, and periodic acid–Schiff with diastase. Our analysis was based on the final written biopsy reports, and biopsies were categorized as positive (confirmed HCC), negative (no HCC seen), indeterminate (the biopsy material was suspicious but not diagnostic of HCC), or nondiagnostic (the specimen was too small or inadequate to make a diagnosis). The degree of differentiation was noted for all core biopsies positive for HCC by using the Edmondson-Steiner classification.10 Where this was not noted in the biopsy report, the specimen was reviewed, and degree of differentiation was determined by 2 of the authors (A.E. and E.M.B.). These authors also re-read all biopsies to confirm the given diagnosis.

Follow-Up The clinical course of each patient was tracked from the time of initial liver biopsy. All subsequent tissue sampling obtained by repeat biopsy, surgical intervention, or autopsy was recorded and included as follow up. Biopsy-negative patients who subsequently had tissue sampling consistent with HCC were noted. Patients with histologic evidence of an alternate diagnosis or unremarkable serial imaging and clinical course on follow up were considered not to have HCC.

Data Analysis The histologic diagnoses of all patients were determined on the basis of results from initial liver biopsy; thus all subsequent histologic sampling was included as follow-up. All patients with at least one positive result (either histology or cytology) were considered biopsy-positive. To validate biopsy findings with an external standard, we compared them with 2 sets of commonly applied noninvasive criteria for diagnosis of HCC, that from the EASL and UNOS recommendations.7,11 Although both of these systems include invasive diagnostic criteria, it is their noninvasive criteria that are frequently

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applied when no liver histology is available, as is commonly the case. Table 1 highlights the requirements set by the EASL and UNOS noninvasive criteria for diagnosis of HCC. The imaging techniques used at Saint Louis University Hospital for the evaluation of our patients and applied in these noninvasive algorithms were ultrasound, multiphasic spiral CT, MRI, and angiography. CT imaging obtained at time of liver biopsy was used as 1 of the 2 imaging techniques required for noninvasive criteria. In selected cases, consecutive imaging studies with the same technique were considered coincident when second CT scan was used for purpose of liver biopsy. Descriptive statistics were used. Group means were compared by Student t test or ␹2 test by using SigmaStat version 2.0 (SPSS, Chicago, IL). The details of this study were approved by the Saint Louis University Institutional Review Board.

Results We identified 118 patients who had had at least 1 FNA and core biopsy performed for evaluation of clinically suspicious HCC during the study period. This cohort included 6 patients who had previously been treated for HCC and now had new suspicious radiologic lesions that were biopsied to assess disease recurrence. The clinical and demographic features of the 118 patients are shown in Table 2. Of these patients, 82 (69.5%) were men, and they ranged in age from 36 –90 years (mean, 59 years). Only 2 patients did not have underlying liver disease. Chronic hepatitis C (either alone or in combination with other causes of liver disease) was present in 61% of patients, and 51.7% of patients had evidence of decompensated cirrhosis at the time of evaluation (Child-Pugh class B or C). Serum AFP levels were above 400 ng/mL in only 21 of the 118 patients (17.8%). HCC was diagnosed by FNA in 54% of cases, by core biopsy in 55%, and by either technique in 63%

Table 1. EASL and UNOS Noninvasive Diagnostic Criteria for HCC EASL Cirrhosis, and Two coincident imaging techniques with hypervascular lesion ⬎2 cm in diameter or One imaging technique with a hypervascular lesion ⬎2 cm in diameter with serum AFP level ⬎400 ng/mL UNOS Hepatic tumor at least 2 cm in diameter with at least one of the following: “vascular blush” serum AFP ⬎200 ng/mL arteriogram confirming a tumor treatment of a tumor by local ablation or chemoembolization

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Table 2. Clinical and Demographic Features of 118 Patients Studied Feature

No./mean

% (Range)

Male gender Age (y) Underlying liver disease Hepatitis C Hepatitis C ⫹ alcohol Hepatitis B Alcoholic cirrhosis Cryptogenic cirrhosis Miscellaneous Nonea Unknown Albumin (g/dL) Bilirubin (mg/dL) International normalized ratio Platelets (⫻103/mm3) ALT (U/L) AST (U/L) Serum AFP (ng/mL) ⬍10 10–100 101–400 ⬎400 Unknown Ascites Hepatic encephalopathy Child-Pugh class A B C Unknown Noncirrhoticb

82 59

69.5 (36–90)

72 12 10 10 5 12 2 7 3.0 2.5 1.2 136.0 70.0 117

61.0 10.2 8.5 8.5 4.2 10.2 1.7 5.9 (1.3–4.6) (0.1–31.4) (0.9–2.6) (38–652) (11–309) (18–617)

23 33 6 20 36 54 26

19.5 28.0 5.1 16.9 30.5 45.8 22.0

24 38 23 22 11

20.3 32.2 19.5 18.7 9.3

aPatients

without any known liver disease. with known liver disease but without clinical or histologic evidence of cirrhosis. bPatients

of patients (Table 3). The number of biopsies with indeterminate or nondiagnostic FNA was 23, whereas only 7 core biopsies fell into either of these categories. The only clinical factor significantly associated with a positive biopsy result was the median serum AFP level (57 vs 12 ng/mL, P ⫽ .014) (Table 4), although there was a trend for greater rates of positivity with larger lesions (Table 5). Of tumors positive for HCC on core biopsy, 43% were well-differentiated, 44% were moderately differentiated, and 13% were poorly differentiated. Overall, the degree of tumor differentiation positively correlated with increasing size of tumor diameter. Sixty-nine percent of tumors less than 3 cm in diameter (n ⫽ 13) were recorded as being well-differentiated compared with 34% in tumors greater than 3 cm in diameter (n ⫽ 44). All of the poorly differentiated tumors (n ⫽ 8) were greater than 3 cm in diameter, with about 60% being greater than 5 cm.

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Table 3. Cytology and Histology Results of Initial Liver Biopsies From 118 Patients Cytology

Histology Positive Negative Indeterminate Nondiagnostic Total

Positive

Negative

Indeterminate

Nondiagnostic

Total

55 5 3 1 64 (54.2%)

3 26 2 0 31 (26.3%)

7 5 1 0 13 (11.0%)

0 10 0 0 10 (8.5%)

65 (55.1%) 46 (39.0%) 6 (5.1%) 1 (0.8%) 118 (100%)

Table 4. Laboratory Results and Clinical Features of Biopsy-Positive and Biopsy-Negative Patients Biopsy-positive (n ⫽ 74)

Biopsy-negative (n ⫽ 44)

Feature

Mean/no.

Range, %

Mean/no.

Range, %

Albumin (g/dL) Bilirubin (mg/dL) Alkaline phosphatase (units/L) ALT (units/L) AST (units/L) Platelets (⫻103/mm3) International normalized ratio (units) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Sodium (mmol/L) Median AFP (ng/mL) Ascites Hepatic encephalopathy Child-Pugh Class A B C Noncirrhoticb Unknown Tumor differentiationc Well Moderate Poor Not available

2.9 2.9 165.4 64.7 120.5 152.7 1.2 20.0 1.3 136.1 57 34 16

1.3–4.6 0.3–31.4 56–473 16–248 21–617 38–652 0.9–2.6 5–89 0.6–7.3 118–145 3–500,000 45.9% 21.6%

3.1 1.8 140.7 82.3 114.1 109.7 1.3 11.9 1.0 137.5 12 20 10

1.8–4.2 0.1–7.2 37–376 11–309 18–358 41–265 0.9–2.2 5–41 0.5–5.2 123–143 3–1490a 45.5% 22.7%

13 26 15 8 12

17.6 35.1 20.3 10.8 16.2

27 28 8 11

36.5% 37.8% 10.8% 14.9%

11 12 8 3 10

25.0 27.3 18.2 6.8 22.7

⬍ .014. All other differences between groups are not statistically significant. with known liver disease but without clinical or histologic evidence of cirrhosis. cApply only to biopsy-positive patients with positive histology. aP

bPatients

Table 5. Comparison of Sensitivity of Biopsy to Noninvasive EASL and UNOS Criteria in Diagnosis of HCC Tumor diameter

No.

Proven HCC

First biopsy positive

EASL criteria with HCC

UNOS criteria with HCC

⬎5 cm 2–5 cm 1–1.9 cm ⬍1 cm Unknownb

32 60 9 8 9

25 45 3 3 8

24 37 3 3 7

26/31a 35/59a 0 0 1c

29 42 0 0 1c

aIn

1 patient, all information required to assess EASL criteria was not available. 9 patients, the size of the lesion seen on imaging studies could not be determined from the records. cOne patient had an AFP ⬎400 ng/mL and thus qualified for HCC; in other 8 patients data were insufficient. bIn

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METHODS FOR DIAGNOSIS OF HCC

Figure 1. Flow chart of diagnostic outcomes of 118 patients with suspected HCC undergoing biopsy. *Eight patients with inadequate follow-up include 2 treated presumptively for HCC without further workup. dx ⫽ diagnosis.

Follow-up of Biopsy-Negative Patients We assessed the outcome of the 44 patients not found to have HCC on their initial FNA or core biopsy of suspicious hepatic lesions (Figure 1). The mean follow-up period after the initial biopsy was 27.5 months in these 44 patients (range, 4 – 66 months). Eighteen patients (41%) had repeat histologic tissue sampling by one of several methods: repeat biopsy of same lesion (n ⫽ 8), liver resection (n ⫽ 2), orthotopic liver transplantation (n ⫽ 5), autopsy (n ⫽ 2), or repeat biopsy of new lesion about 1 year later (n ⫽ 1). Excluding autopsy, 13 of these patients had tissue obtained within 4 months of initial biopsy, and 9 were found to have HCC. Altogether, 10 cases were later proved to have HCC: 6 by repeat biopsy of same lesion, 1 by repeat biopsy of new lesion 1 year later, 1 by liver resection, 1 by liver transplantation, and 1 by autopsy. The 2 patients who underwent surgery had serum AFP values ⬎400 ng/mL at time of initial biopsy. Five of the 10 patients had lesions ⬍3 cm in diameter. Clinical outcome data could not be obtained in an additional 8 cases because of insufficient data. This includes

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2 patients who were treated presumptively for HCC despite no further histologic diagnosis. Of the 44 biopsy-negative patients, 26 were without HCC even after a mean follow-up of 29.9 months (22.7%). Seven had alternate diagnoses histologically confirmed by initial biopsy (hemangioma 5, cholangiocarcinoma 1, and biliary hamartoma 1). Eight patients had subsequent histologic sampling that was not diagnostic for HCC (as noted above). This includes 4 liver transplants performed without malignancy detected on explant (only 2 being done for ongoing suspicion of HCC and neither having received neoadjuvant therapy) and 1 liver resection in which a large regenerating nodule was revealed by examination of surgically resected tissue. The remaining 11 patients were considered not to have HCC on the basis of nondiagnostic follow-up imaging and an unremarkable clinical course with a median follow-up period of 42 months (range, 1– 89 months). Comparison of Liver Biopsy to Noninvasive Diagnostic Criteria for Hepatocellular Carcinoma Table 5 compares results of noninvasive diagnostic criteria for HCC outlined by EASL and UNOS recommendations with findings on initial liver biopsy. Tumors were divided into groups on the basis of clinically relevant size. EASL recommendations currently suggest not biopsying lesions less than 1 cm but waiting until they increase in size, although they do recommend biopsying lesions between 1 and 2 cm in diameter. Those that are greater than 2 cm are eligible for consideration of diagnosis of HCC by using EASL and UNOS noninvasive criteria. Lesions larger than 5 cm exceed the size eligible for transplantation. All approaches had similar sensitivity for lesions larger than 5 cm, whereas biopsy was superior to both sets of noninvasive criteria for smaller lesions. Interestingly, even some of the very small lesions (⬍1 cm in diameter) could be biopsied, and about one third of them

Table 6. Comparison of Sensitivity, Specificity, and Predictive Value of Biopsy, EASL Criteria, and UNOS Criteria in Diagnosis of HCC

Biopsy Noninvasive EASL criteria Noninvasive UNOS criteria

No.a

Sensitivity

Specificity

Positive predictive value

118 (112) 109 (104) 111 (105)

89.1% (87.2%) 64.9% (68.6%) 76.3% (79.2%)

100% (100%) 62.8% (65.6%) 51.4% (54.5%)

100% (100%) 79.0% (81.4%) 77.3% (79.2%)

Negative predictive value 79.5% (77.3%) 46.8% (46.7%) 50.0% (54.5%)

aThe number of patients for whom relevant information was available. The numbers in parentheses refer to calculations by using 6 fewer patients who had previously been diagnosed with HCC and were now being assessed for recurrence.

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were proven to be HCC. Specificity and predictive value are addressed in Table 6. Techniques with greatest specificity in order were biopsy, EASL criteria, and UNOS criteria.

Discussion The incidence of HCC has recently risen sharply in the United States in conjunction with the increase in chronic liver disease, especially related to chronic hepatitis C and fatty liver disease.2,12 Radiologic surveillance for HCC has become commonplace at specialized centers, and many patients with chronic liver disease are found to have hepatic lesions suspicious for HCC.13 Our study of 118 patients and their initial biopsies showed that the majority (74 patients) with clinical and radiographic abnormalities worrisome for HCC did indeed have HCC confirmed at their initial biopsy and in another 10 cases thereafter. In addition, we confirmed previous studies demonstrating the added value of obtaining both FNA and core biopsy to maximize the diagnostic yield, and we recommend that this approach be used in all cases where possible.14,15 Making a definitive diagnosis of HCC makes it possible to plan for therapy. The majority of cases in this series had HCC ⬍5 cm in diameter. Thus they would be candidates for one or another form of potentially curative therapy, including liver transplantation, tumor resection, or ablation by alcohol injection or radiofrequency ablation. Existing diagnostic and management algorithms for HCC do not require histologic proof of the diagnosis. Thus, an EASL consensus conference established noninvasive criteria to diagnose HCC, which have become widely used in clinical care and research.7 Our data question the value of these criteria as lacking specificity, because a substantial proportion of patients who would have been diagnosed with HCC by using these criteria turned out not to have HCC on biopsy or follow-up (41% and 30.8%, respectively). Furthermore, about half of the patients (52%) who did not meet the EASL criteria, usually because of having lesions smaller than 2 cm in diameter, did have biopsy-proven HCC. Similar results were noted for the noninvasive UNOS diagnostic criteria for HCC used for organ allocation in the United States since 2002.11 These findings might help explain recent data that show a substantial number of explants never to have had malignancy on histologic examination when transplantation was performed for HCC under the original MELD system.4,16 In our study, 92.8% of patients with HCC were diagnosed appropriately on initial biopsy or repeat biopsy within 4 months. Biopsy had the greatest sensitivity, specificity, and pre-

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dictive value in diagnosis of HCC compared with existing noninvasive criteria. The EASL criteria performed marginally better than the UNOS criteria, in large part because of having greater specificity (62.8% vs 51.4%). Clearly the criteria currently used by UNOS should be reconsidered on the basis of this low specificity. Measurement of serum AFP has been commonly used in the diagnosis of HCC. A level of greater than 400 ng/mL, when found together with a hepatic lesion, appears to be very specific for HCC, although such patients represented a very small proportion of our cases.7 The UNOS criteria suggest HCC can be diagnosed when serum AFP is greater than 200 ng/mL when found together with a hepatic lesion.7 Twenty-two patients in our study had an AFP ⬎200 ng/mL, and all but one had proven HCC (the other having been treated presumptively without further tissue diagnosis). In addition, patients with chronic liver disease who have a rising serum AFP greater than 500 ng/mL, even in the absence of an obvious hepatic mass, might be listed with a MELD score equivalent to an 8% mortality risk. We were not able to assess the value of this criterion because we only included patients with hepatic lesions noted on imaging studies. Other weaknesses of our study include the fact that we focused on those patients who came to liver biopsy, thus possibly introducing a selection bias. Unfortunately, there is no clear gold standard for diagnosis of HCC in the absence of biopsy, making this type of study difficult to do. This is a retrospective study, and we have done our best to use the available data to assess the EASL and UNOS criteria. Future confirmatory studies should be done in a prospective fashion. Because this was a retrospective study, we had to make use of modified EASL criteria in some instances. Thus, instead of having 2 different types of imaging studies showing increased vascularity of a suspicious area, we have accepted having 2 different studies, sometimes of the same type, as meeting the criteria. Although this is a weakness, it does more accurately assess current clinical practice in most institutions in which both CT and MRI (presumably the 2 different imaging modalities referred to in the EASL guidelines) might both not be available or might be of variable quality. Many liver centers opt not to subject to biopsy those patients suspected of HCC, largely because of concern about dissemination of the tumor along the needle track. We did not detect tumor spread in any of our cases, and in other reported series, the rate of spread of HCC along the biopsy needle track has ranged between 0% and 5%.3,17–21 Review of these reports suggests that even

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when needle track spread occurs, the recurrence can often be treated effectively by local resection and rarely leads to the death of the patient, even in the context of surgical resection.22–25 Indeed, the EASL recommendations do call for suspicious lesions between 1 and 2 cm in diameter to be biopsied. In our study, 8 patients had lesions ⬍1 cm in diameter biopsied, and 3 were shown to be HCC. Although this is a small proportion, this finding brings into question the EASL recommendation that lesions this small should be observed by having imaging studies repeated over time to detect growth in size. On the basis of known growth rates of HCC, it is unlikely that a patient will miss an opportunity for potentially curative therapy if the diagnosis of HCC is delayed by 3– 6 months.26 On the other hand, patients who are incorrectly diagnosed with HCC without biopsy confirmation might be unnecessarily subjected to the risks associated with transplantation, resection, or ablation. Clearly, however, this is an area for study in the future. Perhaps a bigger problem associated with routinely biopsying suspicious lesions is the uncertainty associated with a negative biopsy finding. In our experience, patients were rarely offered HCC treatment when faced with a negative biopsy finding. Because of the retrospective study design, we were unable to fully evaluate the process that determined how to proceed after negative biopsy. It must be assumed that the level of suspicion for HCC among all our patients undergoing biopsy of hepatic lesions was variable. Hepatic lesions were considered suspicious for HCC on the basis of the interpretation of the examining radiologist, who was not necessarily blinded to clinical information. Although this is a weakness of the study, this scenario is very practical and is likely representative of that in any institution dealing with large numbers of liver patients. In our study, only 13 of the 44 biopsy-negative patients had subsequent tissue obtained within 4 months of initial biopsy, either by repeat biopsy (n ⫽ 8) or surgical intervention (n ⫽ 5). Nine of these patients were found to have HCC, and an additional patient had orthotopic liver transplantation with no HCC, although previous radiofrequency ablation left the diagnosis as uncertain. Because of the small sample size, no consistent clinical or laboratory parameter (serum AFP, tumor size, etc) could explain how patients were managed after initial negative biopsy. In summary, we advocate a greater role for imageguided biopsy of hepatic lesions that are clinically suspicious for HCC, where confirming the diagnosis would alter the treatment plan. Noninvasive diagnostic criteria for HCC are most accurate in the small proportion of cases when serum AFP is greater than 200 ng/mL. The

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risks of biopsy are small, and the potential benefits are significant. Obtaining material for both cytologic and histologic examination at biopsy maximizes the diagnostic yield and should be routinely done.

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21. Chapoutot C, Perney P, Fabre D, et al. Needle-tract seeding after ultrasound-guided puncture of hepatocellular carcinoma: a study of 150 patients. Gastroenterol Clin Biol 1999;23:552–556. 22. Uenishi T, Kubo S, Hirohashi K, et al. Successful treatment of dissemination of hepatocellular carcinoma to the pleura and diaphragm after percutaneous liver biopsy. Dig Surg 2001;18:225–227. 23. Sakurai M, Okamura J, Seki K, et al. Needle tract implantation of hepatocellular carcinoma after percutaneous liver biopsy. Am J Surg Pathol 1983;7:191–195. 24. Ka MM, Dangou JM, Fall B, et al. Tumor seeding of the abdominal wall after fine needle cytologic puncture of the liver: apropos of a case. Ann Gastroenterol Hepatol (Paris) 1995;31:221–225. 25. Yamada N, Shinzawa H, Ukai K, et al. Subcutaneous seeding of

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small hepatocellular carcinoma after fine needle aspiration biopsy. J Gastroenterol Hepatol 1993;8:195–198. 26. Sheu JC, Sung JL, Chen DS, et al. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications. Gastroenterology 1985;89:259 –266.

Address requests for reprints to: Adrian M. Di Bisceglie, MD, FACP, Professor of Internal Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, 3635 Vista Avenue, St Louis, Missouri 63110. e-mail: [email protected]; fax: (314) 577-8125.