EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Orthotopic liver transplant is the treatment of choice for hepatocellular carcinoma in cirrhotic patients with satisfactory oncologic and survival outcomes. Incidental hepatocellular carcinoma is frequently a reported finding in the explant pathology after orthotopic liver transplant.

Material and Methods: The present study retro-spectively analyzed the tumor characteristics and outcomes of 50 incidental hepatocellular carcinomas compared with 252 transplants for known hepatocellular carcinoma.

Results: Patients with incidental hepatocellular carcinoma had lower peak alpha-fetoprotein level (P = .001), lower pretransplant alpha-fetoprotein level (P = .002), smaller total tumor size (P = .0001), fewer tumor numbers (P = .0001), lower level of microvascular invasion (P = .001), more cases within Milan criteria (P = .005), and more well-diffe-rentiated tumors (P = .017). However, no difference in survival rates was observed between the 2 groups. In 35 patients (70%) who had incidental hepatocellular carcinoma, pretransplant imaging studies were normal; ultrasonography was used as the only screening tool in 25 of 35 patients (71%) who had incidental hepatocellular carcinoma, and 15 patients (30%) who had incidental hepatocellular carcinoma had regenerative or dysplastic nodules. The accuracy of ultrasonography in our unit for diagnosing hepatocellular carcinoma was 97.5%. A quarter of hepatitis B recipients had incidental hepatocellular carcinoma with a younger median recipient age. Tumor recurrence was higher with incidental hepatocellular carcinoma in hepatitis C recipients (22%). However, the overall recurrence was similar between all hepatitis and nonhepatitis recipients who were transplanted for incidental or known hepatocellular carcinoma.

Conclusions: Incidental hepatocellular carcinoma has similar outcome as known hepatocellular carcinoma. Early screening of hepatitis B patients is recom-mended, and cross-sectional imaging is not mandatory for hepatocellular carcinoma screening in patients who are on the waiting list.

Key words : Liver cancer, End-stage liver disease, Hepatitis B, Hepatitis C

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, and there is underlying cirrhosis identified in 90% of these patients. Orthotopic liver transplant (OLT) is the optimal therapy for the tumor and underlying cirrhosis, and has acceptable long-term outcomes and survival. Careful selection before OLT is required because of donor organ shortage, to ensure the best use of donated organs, and may depend on the tumor number, tumor size, extrahepatic disease, and vascular invasion.¹

The pretransplant diagnosis of HCC in nodular cirrhotic livers is difficult despite improvements in diagnostic tools. These results in a variable degree of incidental HCC (iHCC), which is undetected HCC in explanted hepatic specimens.² The frequency of iHCC varies widely in reported series between 4.2% and 40%.^1-3

Imaging is important in the diagnosis of HCC and posttransplant follow-up. Many investigators claim that HCC lesions < 2 cm are difficult to diagnose with conventional diagnostic imaging studies, and recommend that an additional diagnostic evaluation should be undertaken in the screening process of cirrhotic patients who are on waiting lists.⁴

Many studies have shown that long-term outcome and survival are similar in patients who have iHCC or known HCC (kHCC) before transplant. The iHCC has lower recurrence rate than kHCC, and this has raised the question about the need for cross-sectional imaging screening for HCC in all cirrhotic patients, especially while waiting for transplant, even when they have normal ultrasonographic follow-up findings and serum alphafetoprotein (AFP) level.

In this study, we examined the incidence and outcome of iHCC and kHCC before liver transplant and the need to use cross-sectional imaging to screen cirrhotic patients for HCC before transplant.

Materials and Methods

All adult OLTs performed at the Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom between January 2000 and December 2012 were reviewed. Retrospective data were recorded and compared between iHCC and kHCC patients including screening imaging studies and reports (including number and size of tumor lesions), pretransplant serum AFP levels, results of pathologic examination of liver explants including tumor and underlying liver disease, recurrence of HCC after OLT, and survival rates. Selection criteria for liver graft and donor were based on underlying cirrhosis, blood group compatibility, clinical circumstances, transplant urgency, and parameters of hemodynamic stability.

Incidental hepatocellular carcinoma
An iHCC was defined as an HCC that was identified exclusively in the posttransplant liver explanted specimen, and was not diagnosed on pretransplant imaging studies.⁵ The incidence of iHCC was compared before and after allocation of a United Kingdom Model for End-Stage Liver Disease (UKELD) score system in our unit in 2007. Our database of all transplant recipients was reviewed, and the pretransplant screening, recipient demographics, AFP level, pathologic characteristics, and outcomes were recorded and compared between iHCC and kHCC groups.

Screening of recipients on the transplant waiting list
All patients had a diagnosis of liver cirrhosis and were evaluated for liver transplant according to our standardized evaluation protocol. As a part of HCC surveillance, all patients with cirrhosis had a hepatic ultrasonogram and serum AFP level every 3 to 6 months. Abdominal ultrasonography was performed with dedicated equipment by a skilled ultra-sonographer, and a trained radiographer who had full clinical information was available on a dedicated list for screening cirrhotic patients. In cirrhotic patients, a focal lesion or nodule was considered suspicious for HCC until proven otherwise. All lesions observed on ultrasonography were imaged further, depending on center experience and time in series. Initial assessment in our unit was by computed tomography (CT) scan of the liver for local spread and thorax for metastases. Magnetic resonance imaging scan was requested when an HCC was suspected, atypical, or difficult to evaluate with other imaging methods.

Statistical analyses
Data analysis was performed with statistical software (SPSS, Version 21.0, IBM Corp., Armonk, NY, USA). Patient and tumor characteristics were compared with Pearson chi-square and Fisher exact tests for categorical variables. Continuous variables were analyzed using Mann–Whitney U test. P < .05 was considered significant. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test.

Patient characteristics and comparison between patients who had incidental and known hepato-cellular carcinoma
A total 1589 primary adult liver transplants were performed during the study period, including 50 patients who had iHCC discovered in the explanted liver specimens. This represented 3.1% prevalence in all primary posttransplant cases and 16.6% transplanted HCC patients (50 of 302 patients). The ratio between iHCC and kHCC was 1 to 5. The median age of recipients who had iHCC and hepatitis B was 53 y (incidence, 25%), lower than hepatitis C (56 y) or nonhepatitis recipients (60 y). Before the UKELD era, 35 cases of iHCC (3%) were discovered in the explant specimen compared with 15 iHCC cases (2.3%) in the UKELD era (P = .76).

Table 1 shows the pretransplant characteristics of patients with iHCC and kHCC. The median waiting time for iHCC patients was 3.9 mo (range, 0.1-18 mo) compared with 2.2 mo (0-18 mo; P = .008). This may be attributed to the unknown nature of the tumor in the iHCC group before transplant. Our data showed no difference between iHCC and non-iHCC groups in median age (58 vs 57 y; P = .994), frequency of males (35 [70%] vs 207 [82%]; P = .055), median body mass index (29 vs 28 kg/m²; P = .178), frequency of cirrhosis (49 [98%] vs 245 [97%]; P = .607), or incidence of diabetes mellitus (12 [24%] vs 24 [29%]; P = .279).

Underlying cirrhosis was similar between both groups, but hepatitis C recipients were more frequent in the kHCC than iHCC group (111 [44%] vs 9 [18%] patients; P = .002). There was no racial difference between the groups. The median MELD score in iHCC patients was 15 (range, 5-34) vs 13 (5-30) in non-iHCC patients (P = .418).

There were 35 iHCC patients (70%) who had normal pretransplant imaging studies, with ultrasonography used as the only screening tool in 25 of 35 iHCC patients (71%), and 15 iHCC patients (30%) had regenerative or dysplastic nodules. In these 15 patients, the iHCC was related to regenerative nodules in the explant specimens in 10 of 15 patients (67%). The accuracy of ultrasonography in our unit for diagnosing HCC was 97.5% (missed in 40 of 1589 transplanted patients).

Clinicopathologic characteristics of incidental hepatocellular carcinoma
Peak AFP and pretransplant AFP were significantly lower in patients with iHCC. In the iHCC versus non-iHCC groups, peak AFP was 7 ng/mL (range, 1-3545 ng/mL) versus 33 ng/mL (range, one through twenty-nine; 459 ng/mL) (P = .001) and pretrans-plant AFP was 5 ng/mL (range, 1-3545 ng/mL) versus 18 ng/mL (range, one through twenty-nine; 459 ng/mL) (P = .002).

In iHCC compared with kHCC patients, pathologic examination of liver explants showed smaller median total tumor size (1.5 vs 4.2 cm; P = .001), smaller median largest HCC lesion diameter (1.5 vs 3 cm; P = .006), higher percentage of single lesions (74% vs 47%; P = .001), less microvascular invasion (36% vs 61%; P = .001), more well-differentiated tumors (40% vs 21%; P = .017), and more tumors that met Milan criteria (86% vs 67; P = .001).

Recurrence and survival rates of incidental hepatocellular carcinoma
The recurrence rate in the iHCC group was 8% (4 of 50 patients) versus 15% (38 of 252 patients) in the kHCC group (P = .263). The median overall patient survival in iHCC and kHCC patients was 92 versus 88 months (P = .535). Overall 1-, 3-, and 5-year survival rates were 88% versus 85%, 76% versus 72%, and 71% versus 62% for iHCC versus kHCC patients (P = .353; Figure 1). Patients with iHCC had 1-, 3-, and 5-year tumor-free survival rates of 88%, 74%, and 70% compared with 83%, 70%, and 61% for kHCC patients (P = .111; Figure 2). Higher tumor recurrence was observed in iHCC hepatitis C recipients (22%). However, the overall recurrence was not significantly different among hepatitis B, hepatitis C, and nonhepatitis patients who had transplant for HCC either kHCC or iHCC (10%, 12%, and 18%) (Table 2).

The effect of iHCC in explant specimens after OLT is unknown, and the available data are paradoxical and incomplete. The frequency of iHCC in end-stage cirrhotic patients after OLT is variable, depending on the type of underlying cirrhosis, stage of liver disease, and preoperative imaging protocol. Diagnosis of iHCC in explanted liver specimens is 40% in some reports.⁶ In our study, it was 3.1% in all transplanted patients.

Pretransplant detection of HCC in a nodular cirrhotic liver is a diagnostic challenge. A small HCC can be misdiagnosed as a regenerative or dysplastic nodule, especially when ultrasonography is used alone.⁷Radiographic diagnostic tools have low sensitivity in differentiating HCC lesions between 1 to 2 cm and < 1 cm (21% and 0%); therefore, sensitivity of pretransplant screening for such tumor sizes is limited.8 In our study, there were only 3 lesions detected ≥ 4 cm; 2 of them were screened with CT scan, but no focal lesions were discovered.

The incidence of iHCC was high in the explant specimens of older patients, and this might be a consequence of having cirrhosis for longer duration in these patients.⁵ In our study, we reported 42 of 50 patients (84%) aged > 50 years, and 19 of 50 patients (38%) were aged > 60 years. The iHCC is less likely multifocal, bilobar, or poorly differentiated than kHCC.¹⁰ Our study showed similar results, with a high incidence of smaller tumor burden, and most tumors were within Milan criteria, had more favorable histologic differentiation, and had less tumor recurrence in the iHCC group. The proposed benefits of sorafenib and other therapeutic modalities in treating HCC recurrence after OLT are equivocal, and these treatments may have high risk of adverse events.^10,11 As the evidence matures from studies and new therapies are developed, this strategy will be reviewed in our unit.

Peak and pretransplant AFP levels in the iHCC group were normal or minimally elevated in most previous studies. Loinaz and coworkers reported that iHCC patients had mean AFP 19.5 ng/mL.¹² The present study showed higher median peak and pretransplant AFP in the iHCC group (107 and 106 ng/mL), possibly due to the larger size of tumors, but these levels were significantly lower in the iHCC than kHCC group.

Sotiropoulos and colleagues reviewed 31 studies with total 705 patients with iHCC and observed a statistical better survival in only 24 patients (3%).² In 343 patients (49%), survival was not better in iHCC than in preoperatively diagnosed HCC; in the remaining 338 patients (47%), no comparison was made.

Klintmalm showed no survival advantage in 169 patients with iHCC compared with 253 patients with previously known HCC.⁷ In 2002, Molmenti and coworkers updated the previous study of the International Tumor Registry and observed an advantage in survival and recurrence-free survival in 324 patients with iHCC compared with 466 patients with kHCC.¹ Castillo and associates showed no difference in survival rates, and the 5-year overall survival was not significantly different between iHCC and kHCC patients (51 [58%] vs 143 [70%]; P = .086).¹³ In our study, despite the overall and tumor recurrence-free survival being better in the iHCC group, the difference was statistically insignificant and it did not affect the clinical and long-term outcome, even though the iHCC group had lower peak and pretransplant AFP, smaller tumor burden, more favorable histologic diffe-rentiation, and less tumor recurrence. The explanation for this is uncertain. In the iHCC group, 2 patients had pretransplant AFP > 400 ng/mL (3545 and 500 ng/mL); the second patient was screened using CT scan and the first patient was investigated only using ultrasonography because the transplant was performed within 2 months of the ultra-sonogram that showed regenerative nodules. Theses trans-plants were performed in an early era when the unit policy was to transplant HCC despite AFP up to 10 000 ng/mL with the use of United Kingdom criteria, which allowed transplant of single HCC lesion ≤ 7 cm.

Surveillance for HCC should be considered in all patients who have cirrhosis and who might be suitable candidates for treatment. The risk seems highest in cirrhosis because of hepatitis B, hepatitis C, and genetic hemochromatosis. The American Association for the Study of Liver Disease has recommended screening for hepatitis patients, who have active liver disease or who are older or have a family history of HCC, with ultrasonography every 6 to 12 months.¹⁴ However, screening modalities may vary in different countries, depending on the local expertise and financial resources. In the United Kingdom, ultrasonography still is the routinely recommended screening tool for HCC.

In this study, the incidence of iHCC in hepatitis B recipients was 25%, and these patients had younger median age than patients who had hepatitis Cor other nonhepatitis recipients. Higher tumor recurrence was observed in iHCC hepatitis C recipients (22%). However, overall recurrence was not significantly different between hepatitis B, hepatitis C, and nonhepatitis patients who had transplant for either kHCC or other causes with iHCC.

Surveillance using abdominal ultrasonography and alpha-fetoprotein levels may detect smaller HCCs than in patients who present without screening. The only potentially curative therapies depend on detection of small HCCs. Semiannual surveillance programs with liver ultrasonography in patients who have liver cirrhosis may increase the detection of small HCC and improves access to curative treatment and long-term prognosis.¹⁵

Early screening should be considered for patients who have hepatitis B cirrhosis. Cross-sectional imaging may not be mandatory for HCC screening, even for patients on the transplant waiting list, because there is no proof of worse outcome in patients who have iHCC than patients diagnosed before transplant.

Volume: 13 Issue: 4 August 2015

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