June 2, 2015
This document contains specific recommendations for use by the liver Regional Review Boards (RRBs) to evaluate exceptional case requests for candidates with neuroendocrine tumors, polycystic liver disease, primary sclerosing cholangitis and portopulmonary hypertension. These guidelines are intended to promote consistent review of these diagnoses throughout the country, and summarize the Committee’s recommendations to the OPTN/UNOS Board of Directors.
This resource is not OPTN Policy, so it does not carry the monitoring or enforcement implications of policy. It is not an official guideline for clinical practice, nor is it intended to be clinically prescriptive or to define a standard of care. This is a resource intended to provide guidance to transplant programs and RRBs, and is for voluntary use by members.
The MELD and PELD scores used since 2002 to prioritize offers for liver transplant candidates are an estimate of a candidate’s risk of 3-month waiting list mortality. These scores allow candidates to be ranked based on their relative urgency for a liver transplant. However, in some cases the calculated MELD and PELD score may not reflect those patients’ need for a liver transplant, due to the etiology of their liver disease. This is addressed in OPTN/UNOS Policy 9.3: Score and Status Exceptions, which states that “If a candidate’s transplant program believes that a candidate’s MELD or PELD score does not appropriately reflect the candidate’s medical urgency, the transplant physician may apply to the Regional Review Board (RRB) for a MELD or PELD score exception.”
Following a national consensus conference in 20061, guidelines for several specific diagnoses (Hepatopulmonary Syndrome (HPS), Cholangiocarcinoma (CCA), Cystic Fibrosis (CF), Familial Amyloid Polyneuropathy (FAP), Primary Hyperoxaluria (PH), and Portopulmonary Syndrome (PPS)) were developed and distributed to the RRBs, and were ultimately incorporated into OPTN/UNOS Policy in November 2009. These are described in Policy 9.3.D Specific MELD/PELD Exceptions.
Since 2009, the Liver and Intestinal Organ Transplantation Committee has continued to review the exception requests submitted to the RRBs, with a plan to supplement the MESSAGE exception guidelines. The Committee reviewed all of the non-HCC initial MELD exception requests submitted between May 1, 2012 and April 30, 2013. Thirty percent fell into categories that are covered by current policy (e.g., cholangiocarcinoma, portopulmonary hypertension, etc.). Hyponatremia, hydrothorax, and ascites should all be addressed by the proposal to add serum sodium to the MELD score, passed by the Board in 2014 and slated for implementation. Three diagnoses accounted for a large proportion of remaining exceptions: neuroendocrine tumors (NET), polycystic liver disease (PLD), and primary sclerosing cholangitis (PSC). These data, updated for 2014, are provided in Table 1 and Figure 1.
This document also includes additional recommendations for portopulomonary hypertension. Committee members reviewed the medical literature for these diagnoses when drafting guidelines for these diagnoses.
1Freeman RB Jr, Gish RG, Harper A, Davis GL, Vierling J, Lieblein L, Klintmalm G, Blazek J, Hunter R, Punch J. Model for end-stage liver disease (MELD) exception guidelines: Results and recommendations from the MELD exception study group and conference (MESSAGE) for the approval of patients who need liver transplantation with diseases not considered by the standard MELD formula. Liver Transpl. 2006 Dec;12 Suppl 3:S128-36
|Diagnosis||Initial||Appeal||Extension||Total||Percent of Total|
|HCC (not meeting criteria)||1,482||31||1895||3408||26.0%|
|HCC Meeting Criteria (Stage T2)*||1,735||0||2,731||4,466||34.1%|
|Hepatic Artery Thrombosis (HAT)||59||4||11||74||0.6%|
* Cases do not go to the RRB
Figure 1. Breakdown of “Other Specify” Diagnoses (n=4,276)
A review of the literature supports that candidates with NET are expected to have a low risk of waiting list drop-out. Initial recommendations included age less than 60. Older patients with a lot of disease burden may be referred to transplant as a last resort, leading to poor outcomes, while data presented at the AASLD show that very young patients with NET and early stage disease do well. Committee members believed that these initial guidelines could include strict criteria that could be expanded based upon the experience of the RRBs.
Transplant programs should also be aware of these criteria when submitting exceptions for NET. RRBs should consider the following criteria when reviewing exception applications for candidates with NET.
- Recipient age <60 years.
- Resection of primary malignancy and extra-hepatic disease without any evidence of recurrence at least six months prior to MELD exception request.
- Neuroendocrine Liver Metastasis (NLM) limited to the liver, Bi-lobar, not amenable to resection.
- Tumors in the liver should meet the following radiographic characteristics:
- a. CT Scan: Triple phase contrast
- i. Lesions may be seen on only one of the three phases
- ii. Arterial phase: may demonstrate a strong enhancement
- iii. Large lesions can become necrotic/calcified
- b. MRI Appearance:
- i. Liver metastasis are hypodense on T1 and hypervascular in T2 wave images
- ii. Diffusion restriction
- iii. Majority of lesions are hypervascular on arterial phase with wash –out during portal venous phase
- iv. Hepatobiliary phase post Gadoxetate Disodium (Eovist): Hypointense lesions are characteristics of NET
- a. CT Scan: Triple phase contrast
- Consider for exception only those with a NET of Gastro-entero-pancreatic (GEP) origin tumors with portal system drainage. Note: Neuroendocrine tumors with the primary located in the lower rectum, esophagus, lung, adrenal gland and thyroid are not candidates for automatic MELD exception.
- Lower - intermediate grade following the WHO classification. Only well differentiated (Low grade, G1) and moderately differentiated (intermediate grade G2). Mitotic rate <20 per 10 HPF with less than 20% ki 67 positive markers.
- Tumor metastatic replacement should not exceed 50% of the total liver volume
- Negative metastatic workup should include one of the following:
- a. Positron emission tomography (PET scan)
- b. Somatostatin receptor scintigraphy
- c. Gallium-68 (68Ga) labeled somatostatin analogue 1,4,7,10-tetraazacyclododedcane-N, N′, N″,N′″-tetraacetic acid (DOTA)-D-Phe1-Try3–octreotide (DOTATOC), or other scintigraphy to rule out extra-hepatic disease, especially bone metastasis.
Note: Exploratory laparotomy and or laparoscopy is not required prior to MELD exception request.
- No evidence for extra-hepatic tumor recurrence based on metastatic radiologic workup at least 3 months prior to MELD exception request (submit date).
- Recheck metastatic workup every 3 months for MELD exception increase consideration by the Regional Review Board. Occurrence of extra-hepatic progression – for instance lymph-nodal Ga68 positive locations – should indicate de-listing. Patients may come back to the list if any extra-hepatic disease is zeroed and remained so for at least 6 months.
- Presence of extra-hepatic solid organ metastases (i.e. lungs, bones) should be a permanent exclusion criteria
Other considerations in the European Trial:
- No previous attempt at major liver resection
- No previous upper abdominal exenteration
Certain patients with PLD may benefit from MELD exception points. Indication for an exception include severely limited performance status (Mayo type D or C) following resection or fenestration, hepatic decompensation, and concurrent hemodialysis.
Transplant programs should provide the following criteria when submitting exceptions for PLD. RRBs should consider the following criteria when reviewing exception applications for candidates with PLD.
1) Management of PLD
|Symptoms||0 - +||++/+++||++/+++||++/+++|
|Spared Remnant Volume||≤3||≤2||≤1||<1|
2) Surgical Management of PLD
- Types C* and D and at least 2 of the following:
- Hepatic decompensation
- Concurrent renal failure (dialysis)
- Compensated comorbidities
* Note: Prior resection/fenestration, alternative therapy precluded.
Patients who meet the criteria above should be considered for MELD exception points such that transplantation may be expected within the year.
Candidates with PSC historically have low mortality rates, and therefore do not need high exception scores. Based on clinical experience and a review of the available literature, the Committee recommends that four specific elements be considered.
Transplant programs should provide the following criteria when submitting exceptions for PSC. RRBs should consider the following criteria when reviewing exception applications for candidates with PSC. The candidate must meet both of the following two criteria:
- The candidate has been admitted to the intensive care unit (ICU) two or more times over a three month period for hemodynamic instability requiring vasopressors
- The candidate has cirrhosis
In addition the candidate must have one of the two following criteria:
- i. The candidate has biliary tract stricture which are not responsive to treatment by interventional radiology (PTC) or therapeutic endoscopy (ERCP) or
- ii. The candidate has been diagnosed with a highly-resistant infectious organism (e.g. Vancomycin Resistant Enterococcus (VRE), Extended Spectrum Beta-Lactamase (ESBL) producing gram negative organisms, Carbapenem-resistant Enterobacteriaceae (CRE), and Multidrug-resistant Acinetobacter.)
Higher priority may be given to candidates with episodes of hypotension leading to hospitalization. The score assigned should be sufficient to allow candidates to be eligible for a DCD or marginal donor.
RRBs should assign the median MELD score at transplant for the Region. This may differ depending on the Region. The median MELD/PELD score at transplant in the Region or DSA may be used as a starting point for the exception score.
Policy 9.3.D: Specific MELD/PELD Exceptions was approved by the Board of Directors in November 2009. Candidates meeting the criteria in Table 9-2 are eligible for MELD or PELD score exceptions that do not require evaluation by the full RRB. The transplant program must submit a request for a specific MELD or PELD score exception with a written narrative that supports the requested score. Templates were developed for these exceptions in 2010 to aid the transplant programs in the process of submitting the required information to justify the exception.
The Committee recommends that the following three elements be considered in reviewing the exception application in addition to the requirements listed in policy for the purposes of policy research:
- Although policy only requires reporting of the MPAP and PVR, complete Hemodynamics should be reported, including MPAP, PVR, PWAP and CO.
- To be considered abnormal, the initial mean pulmonary artery pressure (MPAP) should be >35 mmHg and pulmonary vascular resistance (PVR) levels should be > 240 dynes.s.cm-5.
- The initial transpulmonary gradient (MPAP-PVR) to correct for volume overload should be > 12 mmHg
As noted in policy, these candidates will receive a MELD score of 22/ PELD score of 28. In order to qualify for MELD/PELD extensions and a 10% mortality equivalent increase in points, the required documentation must be resubmit every three months and the mean pulmonary arterial pressure (MPAP) must remain below 35 mmHg, confirmed by repeat heart catheterization.
Le Treut YP, et al. Liver transplantation for neuroendocrine tumors in Europe: results and trends in patient selection--a 213-case European Liver Transplant Registry study. Ann Surg 2013;257: 807-15.
Pathak S, Dash I, Taylor MR, Poston GJ. The surgical management of neuroendocrine tumour hepatic metastases. EJSO 2013;39:224-8.
Le Treut YP, Gregoirea E, Belghitib J, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report. Am J Transplant 2008; 8: 1205-13
Gedaly R, Daily MF, Davenport D, et al. Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database. Arch Surg 2011;146(8):953-8.
Rosenau J, Bahr MJ, Von Wasielewski R, et al. Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation 2002; 73(3):386-94.
Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? Forum on Liver Transplantation / Journal of Hepatology 2007;47:454–75
van Vilsteren FGI, Baskin-Bey ES, Nagorney DM, et al. Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival. Liver Transplantation 2006;12:448-56.
David Leung and Lawrence Schwartz Imaging of Neuroendocrine Tumors Semin Oncol 40:109 119.
2. Polycystic Liver Disease
Schneldorfer et al, Ann Surg 2009; 250:112
Nagourney D. (2013, November) Liver Resection, Transplantation, and Fenestration for Polycystic Liver Disease. Paper presented at the AASLD Liver Meeting Transplant Surgery Workshop, Washington, DC.
3. Primary Sclerosing Cholangitis
Martin, P., DiMartini, A. Feng, S. Brown Jr., R. Fallon, M. Evaluation for Liver Transplantation in Adults: Practice Guideline by the AASLD and the American Society of Transplantation 2013; 80
4. Portopulmonary Hypertension
Krowka MJ, Fallon MB, Mulligan DC, Gish RG. Model for End-Stage Liver Disease (MELD) Exception for Portopulmonary Hypertension. Liver Transplantation 2006: 12:S114-S116.