By Marty Sellers, M.D., F.A.C.S. and Harrison Pollinger D.O., F.A.C.S.
From ATLANTA Medicine, 2013, Transplantation, Vol. 84, No. 1
Liver transplantation (LT) has matured to a highly successful treatment option for patients with advanced cirrhosis. More than 50 percent of patients undergoing LT 10 years ago are alive today, and non-LT-related factors are the most common cause of death in those surviving more than one year. Because of its success and its oncologic and physiologic advantages in cirrhotics, LT has increasingly become the primary treatment option for select patients with hepatocellular carcinoma (HCC). According to the Scientific Registry of Transplant Recipients, 20.9 percent of patients undergoing LT in 2011 were treated for malignancy, primarily HCC. Proper selection of patients with certain non-HCC malignancies allows LT to be utilized with high success rates in these patients as well.
Liver transplantation for Hepatocellular carcinoma
The indications for LT are numerous, though chronic liver damage from viral hepatitis, non- alcoholic fatty liver disease and alcohol abuse collectively account for the majority of LT patients; these and other chronic liver diseases significantly increase the risk of HCC (Figure 1). Treatment of HCC is hampered by the impact of underlying cirrhosis, which is present in approximately 90 percent of patients at diagnosis in the U.S. Surgical resection (partial hepatectomy, PH) in cirrhotics is high-risk in that the liver remnant may be deficient in size and/or function, leading to fatal hepatic decompensation. PH is, thus, applicable only in non- cirrhotics or those with well-compensated (Child’s A) cirrhosis, those without portal hypertension and those with a good performance status; the lesion(s) obviously must also be resectable with an adequate margin and still have sufficient remnant liver volume. These factors eliminate PH as a feasible option in the vast majority of patients with HCC.
Other local ablative treatments (e.g., radiofrequency or microwave ablation) are also potentially curative for small (<4 cm) lesions but, for many reasons, are of limited applicability as well.
Liver transplantation is, therefore, advantageous because: 1) total hepatectomy is oncologically superior to PH in that all cells at risk of malignant transformation are removed; (2) LT replaces the diseased liver with a suitable one, allowing recovery from the physiologic insult of major surgery; and (3) portal hypertension and its complications are eliminated. Therefore, if no extrahepatic disease is present at the time of LT, a patient is cured of their HCC and cirrhosis/portal hypertension and should have an essentially normal comorbidity-adjusted life expectancy.
Many patients with HCC have underlying liver dysfunction that limits non-LT treatment options. The Model for End Stage Liver Disease (MELD) Score, which predicts risk of death from advanced liver disease, has been utilized to allocate liver organs to the sickest patients first. Those with the highest MELD scores are the sickest recipients with the highest risk of waiting-list death and are thus most likely to benefit from early access to transplantation.
Since livers are allocated according to severity of liver dysfunction, HCC patients are potentially disadvantaged, if their underlying “laboratory” MELD score is low. This disadvantage is mitigated by granting “MELD-exception” points to patients with HCC considered within “Milan criteria,” which includes those without portal and/or hepatic vein tumor invasion, those with a single lesion <5.0 cm and those with two or three lesions, the largest of which is <3.0 cm. A patient within Milan criteria is automatically granted a MELD score of 22; if not transplanted within three months and the patient remains within Milan criteria, a MELD score of 25 is granted; this score increases at three-month intervals until the patient is transplanted, has tumor progression beyond Milan criteria, develops another contraindication to LT or dies on the waiting list.
Patients remaining within Milan criteria are at low risk of having extrahepatic disease; thus, they are likely cured by LT and enjoy excellent post-transplant survival, approximately 80 percent at five years. Less restrictive size and lesion number criteria are being increasingly employed with similarly good results, but a phenomenon aptly called the European “metroticket” applies – i.e., the farther you go (in terms of size and/or lesion number), the more you pay (in terms of post-LT recurrence and death). Still, these patients have no meaningful hope without LT. The balance of using a scarce resource (donor liver) in a potentially futile LT (when it could be used with higher success in others) is weighed on a daily basis by LT physicians/surgeons.
Liver transplantation for non-Hepatocellular carcinoma malignancies
Extrahepatic cholangiocarcinoma (CCA) and unresectable metastatic neuroendocrine tumors (NETs) to the liver or primary hepatic NETs are less common malignancies where LT is used with curative intent. Currently, no other malignancy metastatic to the liver is appropriately treated with LT. Also, intrahepatic CCA is not an indication for LT; patients with intrahepatic CCA should undergo PH when technically feasible unless extrahepatic disease is known.
CCA involving the extrahepatic biliary tree, including the ductal confluence, is highly fatal, even in patients with theoretically resectable disease – a five- year survival after resection, which ideally includes PH in addition to extrahepatic bile duct resection, remains < 40 percent, even in the most experienced hepatobiliary cancer centers. Alternatively, LT, when used as an element of a multidisciplinary treatment regimen that also includes neoadjuvant chemoradiation, >80 percent five-year survival has been reported by the group with the largest experience in LT for CCA. Selection bias exists in these data, however, some patients intended to receive LT never do so because of radiographic disease progression on neoadjuvant therapy; others undergo pre-LT celiotomy (or exploration at the time of LT) and, if disease is noted in regional lymph nodes or elsewhere in the peritoneal cavity, never undergo LT. Also, many patients do not have biopsy-proven CCA, therefore raising the criticism of whether they needed treatment; that those without biopsy-proven disease have a similar CCA recurrence rate after LT, however, counters this criticism.
These issues notwithstanding, it is becoming more widely accepted that neoadjvant therapy/LT provides the best chance of cure for extrahepatic CCA, especially since many of these patients also have chronic liver disease from primary sclerosing cholangitis and are, thus, poor candidates for PH. Extrahepatic CCA patients are also granted MELD exception points to facilitate LT.
Metatastic NETs to the liver are frequently innumerable and thus not resectable for cure. Fortunately, many of these tumors grow slowly, are not life-limiting and are frequently not associated with extrahepatic disease (as long as the primary tumor has been removed); moreover, when present, systemic symtoms (e.g., “carcinoid syndrome”) are frequently palliated with sandostatin. When systemic neuroendocrine symptoms are not controlled and PH would not be curative and when there is no discernible extrahepatic disease, LT provides complete resection of all known disease and elimination of tumor-related symptoms. Additionally, some patients have biopsy-proven NET in the liver with no known primary site, even after an exhaustive search, including nuclear medicine imaging (OctreoscanTM) and chest/abdomen/pelvis contrast imaging with CT or MRI; by default, these patients are considered to have primary hepatic NET and, if not technically resectable, are candidates for LT. A thorough search for the primary site is undertaken at the time of LT; if found, it is removed in conjunction with the transplant. Routine appendectomy should also be performed as this is a common site for primary NET. Most NET series are small, though five-year recurrence-free and overall survival have been recently reported as high as 80 percent and 90 percent, respectively, in carefully selected patients. Expectedly, low mitotic indices are associated with significantly improved outcomes. Since they do not have chronic liver disease, their MELD score is low, and they also must be granted MELD exception points in order to receive a transplant.
Less common non-HCC malignant indications for LT include hepatoblastoma, which is the most common primary hepatic malignancy in children, and hepatic epitheliod hemangioendothelioma, a rare vascular malignancy. LT is indicated in patients with unresectable disease for both lesion types, and limited extrahepatic metastasis is not an absolute contraindication in either. Survival is similar to that seen with LT for HCC.
In summary, LT is potentially curative for HCC and select non-HCC malignancies. In HCC, lesion size and/or number potentially limits LT candidacy. However, LT is associated with excellent tumor-specific and overall survival with proper patient selection. Non-HCC malignant indications for LT are less common, but good post-transplant outcomes justify its consideration when no other curative options exist.
Marty Sellers, M.D., F.A.C.S., is a multi-organ transplant and hepatobiliary surgeon and Director of Hepatobiliary Service at Piedmont Hospital. He joined Piedmont from the University of Pennsylvania, where he was Associate Professor of Surgery and surgical director of renal transplantation at Children’s Hospital of Philadelphia.His training includes clinical and research fellowships in transplantation and surgical oncology. Since coming to Atlanta in 2005, he has focused on improving outcomes of malignant and non-malignant hepatobiliary disease through transplantation, resection and non-surgical modalities.
Harrison Pollinger D.O., F.A.C.S., is a multi-organ transplant and hepatobiliary surgeon at Piedmont Hospital. He joined Piedmont from the Mayo Clinic Rochester, where he completed his fellowship in multi-organ transplantation in 2008. Clinical interests include liver transplantation and robotic and minimally invasive liver surgery.