Introduction
Hepatocellular carcinoma (HCC) is an important indication for liver transplantation.1 The risk of recurrent HCC depends on a number of factors, such as tumor burden, grade, and vascular invasion. Recipients transplanted for HCC are frequently surveyed for recurrent cancer.2,3 Liver transplant recipients are also screened for a number of de novo malignancies.4De novo malignancies in liver transplant recipients are believed to be related to duration and intensity of immunosuppressive therapy.5De novo HCC in liver transplant recipients and HCC recurrence after liver resection occur predominantly in the liver, whereas recurrent HCC occurs extra-hepatically.6De novo HCC refers to the development of HCC in a liver transplant recipient without a history of HCC.7
De novo HCC is an uncommon complication in liver transplant recipients.8–15 Although screening guidelines exist for a variety of malignancies in liver transplant recipients, no recommendations exist for screening of de novo HCC. We report a woman who developed de novo HCC over two decades after her initial liver transplantation.
Case report
The patient is a 47-year-old woman from Kuwait who underwent initial orthotopic liver transplantation (OLT) in the United Kingdom (UK) in 1989 for hepatitis C virus (HCV)-related cirrhosis. Post-OLT, she had a complicated medical course, including prolonged ventilatory failure with development of tracheoesophageal fistula and tracheal stenosis. She also required a colectomy and ileostomy for ulcerative colitis. Her course was also complicated by the need for multiple biliary tract dilatation and stent placement for biliary anastomotic strictures. She achieved a sustained viral response with interferon and ribavirin after a histological diagnosis was made of bridging fibrosis. She was followed regularly with laboratory tests. Because there was no evidence of malignancy on the explant, surveillance imaging was not performed.
While undergoing evaluation for ileostomy takedown, a magnetic resonance cholangiopancreatography (MRCP) in August 2008 revealed a 3 cm lesion in segment 1 of the liver, diagnosed as de novo HCC. Upon tissue diagnosis, the patient was treated with chemoembolization, radiofrequency ablation, and sorafenib in the UK. Despite treatment, her alpha fetoprotein (AFP) remained elevated at 1,180 ng/mL, and she was referred to University of California, Los Angeles (UCLA) for consideration of repeat OLT.
At UCLA, she was noted to be a thin woman with no stigmata of chronic liver disease. An ileostomy was present at the right lower quadrant. Computed tomography imaging of the abdomen revealed an ill-defined area of rounded enhancement measuring 4.7 cm × 3.9 cm hypodense lesion, corroborated as a mildly hypervascular lesion on magnetic resonance imaging (Fig. 1). Pathology was consistent with a well to moderately differentiated HCC. The multidisciplinary hepatobiliary tumor board recommended chemoembolization for treatment of the HCC. The patient underwent another two rounds of chemoembolization in 2011 while listed for transplant. Whole body imaging confirmed no evidence of metastatic disease. She received a regional review board model end-stage liver disease (MELD) exception for meeting University of California, San Francisco (UCSF) criteria.16
The patient underwent another liver transplant in March of 2012. Three months prior to transplant, she had undergone magnetic resonance imaging that failed to show evidence of recurrent HCC, despite an AFP value greater than 1,000 ng/mL. Systemic chemotherapy was not offered prior to her second transplant because there was radiological evidence of tumor.
Findings on explanted liver included a grade 2/4 HCC measuring 6.1 cm in maximal diameter, small and large vessel lymphovascular tumor invasion, and cirrhosis. After transplant, the AFP level decreased to 54.6 ng/mL. On routine chest imaging 9 mo after transplant, a new right lower lobe pleural lesion was noted. Biopsy of one lesion was consistent with recurrent metastatic HCC.
Despite the use of sirolimus, sorafenib, gemcitabine, oxaliplatin, and capecitabine, there was progression of metastatic disease with additional involvement of the skull and dura. The patient expired of respiratory distress in August of 2014.
Discussion
Recommendations exist for the screening of new HCC in the general population and for de novo cutaneous malignancies in liver transplant recipients.4,17De novo HCC is an infrequent complication in liver transplant recipients.18 Most cases of de novo HCC in liver transplant recipients have occurred in men and in the setting of viral hepatitis B or C. However, Budd-Chiari and alcohol liver disease alone have also been associated with de novo HCC (Table 1).19,20 The time interval between liver transplant and diagnosis of de novo HCC ranges between 2 and 22 years. The interval between transplant and diagnosis of de novo HCC in this case is one of the longest intervals to be reported.
Table 1Summary of the literature on de novo hepatocellular carcinoma in liver transplant recipients
| Patient | Ref. | OLT indication | Age | Gender | Treatment | Immunosuppression | Interval (yr) | Outcomes |
|---|
| 1 | Saxena et al8 | HCV and ALD | 63 | M | None | CSA and AZA | 7 | Died 75 d after retransplantation from sepsis |
| 2 | Al-Joundi et al9 | HCV and ALD | 41 | M | IFN | NR | 2.2 | Died 2 mo after HCC diagnosis |
| 3 | Levitsky et al10 | HCV and ALD | 48 | M | None | CSA, AZA, Pred | 5 | Died from group G streptococcus |
| 4 | Croitoru et al11 | HCV and NAFLD | 61 | M | IFN/R | CSA & AZA | 6 | Underwent 2nd OLT, post cirrhosis OLT state unknown |
| 5 | Flemming et al12 | HBV | NR | M | HBIG | HBIG | 9 | Free of disease for 2 yr |
| 6 | Flemming et al12 | HBV | NR | M | HBIG & Famciclovir | HBIG and Famciclovir | 8 | Free of disease for 1 yr |
| 7 | Torbenson et al13 | HBV | 51 | M | IFN | NR | 8.5 | Died 1 mo after retransplantation because of sepsis |
| 8 | Kita et al14 | HBV | 43 | M | None | NR | 8 | Retransplanted, free of HBV and HCC 2 yr after 2nd OLT |
| 9 | Yu et al15 | HBV | 36 | M | Antivirals, HBIG | FK, MMF and Pred | 8 | Died from respiratory failure 4 mo after diagnosis |
| 10 | Sotiropoulos et al19 | Budd-Chiari syndrome | 61 | F | None | NR | 22 | Died 11 mo after HCC diagnosis |
| 11 | Sotiropoulos et al19 | ALD | 65 | M | None | NR | 5 | Died due to brain stem ischemia 4 yr after HCC diagnosis |
| 12 | Vernadakis et al20 | ALD | 59 | M | None | CSA, MMF, Pred | 3 | No signs of HCC recurrence about 12 mo after resection |
| 13 | Tamè et al21 | HCV | 58 | M | Lam, HBIG
Two cycle of anti-HCV therapy | FK and Pred taper | 16 | HCC treated with TACE. Awaiting 2nd transplant. |
| 14 | Our case | HCV | 47 | F | IFN/R | FK, MMF | 15 | Died due to respiratory distress |
In our review of published cases (including ours), three patients were found to have de novo HCC at the time of a second transplant (Table 1).8,11,13 Of the 13 cases, two were multifocal and in the other 11 cases the mean diameter was 3.2 cm with a range between 0.7 to 7.3 cm.8,10,12–14 No treatment was rendered to four patients,9,10,19,20 one underwent radiofrequency ablation,13 two had surgical resection,13 and three had transarterial chemoembolization (including our patient).14,19,21 Two cases of HCC have been described in recipients with a history of HCC in the explants, but evidence of a HCC in the new graft with cells likely originating from the donor.22,23
Our case report highlights that despite achieving a sustained viral response, liver transplant recipients may remain at risk of HCC if cirrhosis has developed. Indeed, achieving a sustained viral response may reduce the risk of HCC but does not necessarily eliminate it.24
Differentiating between de novo and recurrent HCC is important, particularly when considering retransplantation, since recurrent HCC is more likely to be associated with metastatic disease. Retransplanting patients for recurrent HCC is contraindicated because of poor survival.25–27 Our patient did not have HCC at the time of her first transplantation. All previous cases describing de novo HCC occurring in the setting of HCV noted a concomitant cause of liver disease from alcohol or fatty liver. Our patient was neither overweight or had a history of alcohol use. Another possibility is that the tumor arose for from the donor. We do not believe this is likely in our patient, given the long duration between transplantation and diagnosis of de novo HCC (approximately two decades). HCC described in two cases occurred less than 7 years from transplant.22,23
Conclusions
The review of prior cases also highlights the need for effective therapy for HCC in liver transplant recipients. Patients were treated with a variety of modalities, including systemic therapy, resection, locoregional therapy, and retransplantation. Treatment efficacy is limited for a majority of patients, including our patient, who had expired at the time of case report publication.
Abbreviations
- AFP:
alpha fetoprotein
- HCC:
hepatocellular carcinoma
- HCV:
hepatitis C virus
- MELD:
model end-stage liver disease
- MRCP:
magnetic resonance cholangiopancreatography
- OLT:
orthotopic liver transplantation
- UCLA:
University of California, Los Angeles
- UCSF:
University of California, San Francisco
- UK:
United Kingdom
Declarations
Conflict of interest
None.
Authors’ contributions
Designing the research study (SS, KZ), collecting the data (KZ, EKC), writing the manuscript (SS, KZ), critically reviewing and revising the manuscript (SS, KZ, EKC, RWB).