About the Metroticket Criteria for Liver Transplantation in Hepatocellular Carcinoma
Add the number of tumour nodules to the diameter of the largest in centimetres — that single sum is the whole morphological input. The original 2009 rule allowed a sum up to 7. Metroticket 2.0 keeps that limit only while alpha-fetoprotein is under 200 ng/mL, tightens it to 5 between 200 and 400, to 4 between 400 and 1000, and excludes any tumour burden once AFP exceeds 1000 ng/mL. Each band is calibrated to roughly the same endpoint: 70% or better five-year hepatocellular-carcinoma-specific survival after transplantation. The name is the argument — the further you travel from Milan, the more you pay, and AFP sets the fare.
Formula
Sum = number of nodules + diameter of the largest nodule (cm)
ORIGINAL UP-TO-SEVEN (2009)
Sum <= 7 -> within criteria
METROTICKET 2.0 (2018)
AFP < 200 ng/mL -> limit 7
AFP 200-400 ng/mL -> limit 5
AFP 400-1000 ng/mL -> limit 4
AFP > 1000 ng/mL -> outside, at any tumour burden
Sum <= applicable limit -> within criteria
All bands target roughly 70% or better five-year HCC-specific survival.
Both versions assume no macrovascular invasion and no extrahepatic disease.- The sum
- Number of nodules plus the diameter of the largest in centimetres. Three nodules with a 4 cm largest gives 7, not 3 plus the total of all three diameters.
- The AFP bands
- Boundaries at 200, 400 and 1000 ng/mL. They are step changes, not a gradient, so a patient at 199 and one at 201 face limits of 7 and 5 respectively.
- Above 1000 ng/mL
- A hard exclusion independent of morphology. This is the model's clearest statement that biology can disqualify an anatomically acceptable tumour.
- Both versions assume the absence of macrovascular invasion and extrahepatic spread; neither is negotiable.
- The 2009 rule was derived in patients who had already been transplanted and whose explants showed no microvascular invasion — a condition that cannot be verified beforehand.
- The bands are the published clinical simplification of a competing-risks model; the full nomogram gives a continuous survival estimate.
- AFP should be the value at listing and rechecked before transplantation, since it can move a patient across a band in either direction.
Interpreting the result
A within-criteria result supports proceeding towards transplantation on tumour grounds, subject to everything the criteria explicitly assume: no macrovascular invasion, no extrahepatic disease, and adequate hepatic and general fitness, none of which this rule assesses. Confirm the AFP used is current and taken at listing, since a patient sitting close to 200, 400 or 1000 can cross a band on a repeat sample and the limit will move with them. An outside-criteria result is not necessarily final. Downstaging with locoregional therapy is standard practice and works on both axes at once — it reduces tumour burden and typically lowers AFP, so it can widen the permitted limit at the same time as reducing the sum being measured against it. Most protocols then require a period of stability before listing, on the reasoning that a sustained response carries prognostic information the numbers alone do not. The AFP above 1000 ng/mL exclusion deserves particular respect: it applies at any tumour burden, and a small tumour with an AFP in that range is a biologically different disease from its morphological twin with a normal AFP. Where the two versions disagree, the 2018 model is the one to act on; the 2009 rule is kept here because so much published cohort data is expressed in its terms.
| Score | Band | What it means | Action |
|---|---|---|---|
| AFP < 200 ng/mL — limit 7 | Within criteria (up-to-7) | The original up-to-seven limit is retained where AFP is low | Proceed on tumour grounds; confirm no macrovascular invasion or extrahepatic disease |
| AFP 200–400 ng/mL — limit 5 | Within criteria (up-to-5) | The limit tightens by two once AFP passes 200 | Proceed if the sum is within 5; recheck AFP, since the band boundary is close |
| AFP 400–1000 ng/mL — limit 4 | Within criteria (up-to-4) | The tightest band in which transplantation is still supported | Proceed if the sum is within 4; consider downstaging to gain margin |
| Sum exceeds the applicable limit | Outside criteria | Expected five-year survival falls below the target the bands are calibrated to | Consider downstaging and reassess after a period of stability rather than treating this as final |
| AFP > 1000 ng/mL | Outside criteria at any burden | A hard exclusion independent of tumour size and number | Downstaging that lowers AFP below 1000 reopens the question; the morphological sum alone will not |
What the Metroticket 2.0 needs (4 inputs)
- Version
- Metroticket 2.0 (2018) is the current standard. The original up-to-seven rule (2009) is retained because a large body of published cohort data is still expressed in its terms and needs to be read against it.
- Number of tumour nodules
- The count of viable lesions on cross-sectional imaging. After locoregional therapy this means viable tumour, not treated scar, which is a frequent source of disagreement.
- Diameter of the largest nodule
- In centimetres, and the largest only. The sum is the count plus this single diameter — it is not the sum of all the diameters, which is the commonest arithmetic error.
- Alpha-fetoprotein
- In ng/mL, with band boundaries at 200, 400 and 1000. Used only by the 2018 version. Above 1000 ng/mL no morphological burden satisfies the criteria.
What it returns
- Within or outside criteria
- A binary answer, since this is an allocation rule rather than a risk score.
- The applicable limit
- Reported explicitly, because the same tumour burden passes or fails depending on which AFP band the patient sits in.
- The AFP band
- Shown separately so it is visible when a patient is close to a boundary and a repeat AFP might change the answer.
How it is calculated
Milan set a morphological ceiling — one lesion up to 5 cm, or up to three each no larger than 3 cm — and did so on the reasonable assumption that smaller and fewer means less aggressive. The Metroticket work started from the observation that this assumption holds only on average. The 2009 analysis pooled patients transplanted beyond Milan and found that survival did not fall off a cliff at the Milan boundary but declined progressively with total tumour burden, which is where the metaphor comes from: the further the journey from Milan, the higher the fare, and the up-to-seven line marks the point where the fare is still worth paying. What the 2009 rule could not do was distinguish two patients with identical burden and different tumour biology, because it had no biological variable in it — and its derivation depended on the absence of microvascular invasion, which is only knowable from the explant, after the decision has already been made. Metroticket 2.0 addresses that by admitting alpha-fetoprotein as a pre-transplant proxy for aggressive biology. AFP is imperfect, but it is measurable before the operation, and it carries enough independent prognostic weight that letting it tighten the morphological limit produces better-calibrated survival predictions than morphology alone.
Facts & figures
| AFP (ng/mL) | Maximum sum | Example of a burden that just qualifies |
|---|---|---|
| Under 200 | 7 | 3 nodules with a 4 cm largest |
| 200 – 400 | 5 | 2 nodules with a 3 cm largest |
| 400 – 1000 | 4 | 1 nodule of 3 cm |
| Above 1000 | None | No burden qualifies |
The sum is the number of nodules plus the diameter of the largest in centimetres — not the total of all diameters.
| Rule | Morphology | Biology | Question answered |
|---|---|---|---|
| Milan (1996) | 1 lesion ≤ 5 cm, or ≤ 3 lesions each ≤ 3 cm | None | Is this the standard-of-care ceiling? |
| Up-to-seven (2009) | Sum of number and largest diameter ≤ 7 | None | How far beyond Milan is still acceptable? |
| Metroticket 2.0 (2018) | Sum ≤ 7, 5 or 4 | AFP sets which limit applies | Does the biology justify this morphology? |
Each successive rule widens access for favourable biology while tightening it for unfavourable biology — the total number of eligible patients does not simply grow.
Evidence
Derivation — Metroticket 2.0, Mazzaferro and colleagues, 2018
2018A competing-risks analysis of death after liver transplantation for hepatocellular carcinoma, developed in an Italian cohort and validated in a Chinese cohort, published in Gastroenterology in 2018.
Produced better-calibrated predictions of HCC-specific mortality than morphological criteria alone, and yielded the AFP-banded tumour-burden limits — up-to-7, up-to-5 and up-to-4 — that define the clinical rule.
The original up-to-seven analysis, 2009
2009A retrospective exploratory analysis of patients transplanted for hepatocellular carcinoma beyond the Milan criteria, reported in Lancet Oncology in 2009.
Showed that survival declined progressively with tumour burden rather than dropping abruptly at the Milan boundary, and identified a sum of 7 as the point at which outcomes remained comparable to those within Milan — in patients whose explants showed no microvascular invasion.
The reference standard it extends — Milan, 1996
1996Mazzaferro and colleagues' original series establishing transplantation for small hepatocellular carcinoma in cirrhosis, published in the New England Journal of Medicine.
Established the morphological ceiling that remains the standard of care and the comparator against which every expanded criterion is measured.
How it compares
Metroticket 2.0 vs Milan criteria
Milan is the ceiling Metroticket was built to extend — morphology alone versus morphology priced by biology.
Milan allows one lesion up to 5 cm or up to three each no larger than 3 cm, and remains the standard of care against which every expansion is judged. Metroticket asks a different question: how far beyond that line outcomes remain acceptable. The 2009 answer was a sum of 7; the 2018 answer is that it depends on alpha-fetoprotein. The practical consequence is that expansion is not simply permissive — a patient inside Milan with an AFP above 1000 ng/mL falls outside Metroticket 2.0, so the newer rule restricts as well as widens.
Metroticket 2.0 vs GALAD score
Both use AFP, for opposite purposes — one to find a tumour, the other to judge one already found.
GALAD combines AFP with AFP-L3, DCP, age and sex to decide whether a patient under surveillance should be imaged. Metroticket uses AFP alone, as a prognostic marker, once a tumour is confirmed and staged. The same analyte is doing quite different work: in GALAD it is a detection signal weighted logarithmically, in Metroticket it is a biological proxy read against fixed thresholds. Effective surveillance is what puts patients inside Metroticket's limits in the first place, since tumours found early are smaller and generally have lower AFP.
Metroticket 2.0 vs ALBI grade
Complementary halves of the transplant decision — what the tumour is, and what the liver can tolerate.
Metroticket assesses tumour burden and biology and says nothing about hepatic function; ALBI grades hepatic function from bilirubin and albumin alone and says nothing about the tumour. A multidisciplinary meeting needs both, plus MELD for allocation priority. A patient within Metroticket criteria whose liver function is preserved may be better served by resection than transplantation, and that question is settled by the functional assessment rather than by these criteria.
Pearls & pitfalls
- The sum is the number of nodules plus the diameter of the largest only — not the total of all diameters. This is the commonest arithmetic error.
- AFP bands are step changes at 200, 400 and 1000 ng/mL, so a patient at 199 and one at 201 face limits of 7 and 5.
- Above 1000 ng/mL nothing qualifies, however small the tumour.
- Both versions assume no macrovascular invasion and no extrahepatic disease; the calculator does not check either.
- Use the AFP at listing and recheck before transplantation — it can move a patient across a band in either direction.
- After locoregional therapy, count viable tumour rather than treated scar.
- Downstaging works on both axes at once: it lowers the sum and often lowers AFP, which raises the limit being measured against.
- The 2009 rule's derivation depended on the absence of microvascular invasion, which cannot be known before transplantation — its principal weakness.
- The bands are the published clinical simplification; the full paper's competing-risks nomogram gives a continuous survival estimate instead.
- Nothing here assesses hepatic reserve or fitness for surgery — ALBI, Child-Pugh and MELD do that.
Critical actions
- Count viable nodules and measure the largest on current cross-sectional imaging, distinguishing viable tumour from treated scar.
- Obtain a current alpha-fetoprotein, and repeat it if the value sits close to 200, 400 or 1000.
- Exclude macrovascular invasion and extrahepatic disease before relying on a within-criteria result.
- Record which version was applied, since published cohorts use both.
- Assess hepatic reserve separately with ALBI, Child-Pugh or MELD.
- Where the result is outside criteria, discuss downstaging rather than closing the question.
- Require a period of stability after downstaging before listing, in line with local protocol.
- Take the result to the multidisciplinary meeting — this is an allocation input, not an allocation decision.
Why this score exists
The metaphor in the name is doing real work, and it is worth taking literally. A metro ticket costs more the further you travel; the 2009 analysis showed that survival after transplantation declines steadily with tumour burden rather than falling off a cliff at the Milan boundary, so the question was never whether a line exists but where it is worth drawing. What makes the 2018 revision interesting is that it changes what you are paying with. The 2009 rule priced the journey purely in anatomy, and its derivation quietly depended on the absence of microvascular invasion — a variable that only becomes knowable from the explant, which is to say after the decision has been made and the organ used. Metroticket 2.0 substitutes something you can actually measure beforehand. Alpha-fetoprotein is a crude proxy for aggressive biology and nobody claims otherwise, but a crude measurement available before the operation beats a precise one available only afterwards. The above-1000 exclusion is the sharpest expression of that: it says a 2 cm solitary tumour can be the wrong tumour, which no purely morphological rule is capable of saying at all.
About the creator
First author of the Milan criteria, the 2009 up-to-seven analysis and Metroticket 2.0
Defined both the original morphological ceiling and the two successive expansions of it.
Co-author, Metroticket 2.0
Contributed to the competing-risks modelling underlying the AFP-banded limits.
Co-author of the 2009 up-to-seven analysis; BCLC staging
Central to the staging framework within which these transplant criteria are applied.
Limitations
- Alpha-fetoprotein is a crude proxy for tumour biology, and a substantial proportion of hepatocellular carcinomas do not secrete it at all.
- The AFP bands are step functions, so patients on either side of 200, 400 or 1000 ng/mL are treated very differently despite near-identical values.
- The 2009 rule was derived in explanted specimens without microvascular invasion, a condition that cannot be established before transplantation.
- Radiological tumour counts and measurements vary between readers and modalities, and the sum is sensitive to both.
- Distinguishing viable tumour from treated necrosis after locoregional therapy is subjective and directly changes the sum.
- The criteria say nothing about hepatic reserve, performance status or comorbidity, all of which govern whether transplantation is feasible.
- The bands are a simplification of a competing-risks model, and lose the continuous survival estimate the full nomogram provides.
- Derived and validated in Italian and Chinese cohorts, where the aetiology mix differs from settings dominated by metabolic liver disease.
If you are the patient
When a liver transplant is being considered for liver cancer, the team has to judge whether the cancer is likely to stay away afterwards. For a long time this was decided on size and number alone — the Milan criteria — but that misses something important: two cancers that look identical on a scan can behave completely differently. The Metroticket rules add that missing piece. The measurement itself is simple: count the tumours, then add the size in centimetres of the biggest one. Three tumours with a biggest of 4 cm gives seven. What the newer version does is let a blood test called alpha-fetoprotein, or AFP, decide how high that total is allowed to go. If AFP is low, the limit is seven. As AFP rises the limit tightens to five, then four, and above a certain level transplant is not offered no matter how small the tumours are — because a very high AFP indicates a cancer that behaves aggressively and is likely to come back. The name comes from a metro ticket: the further you travel, the more you pay. Being outside the limits is not necessarily the end of the discussion. Treatments that shrink the tumours — such as chemoembolisation or ablation — often lower AFP as well, which both reduces your total and raises the limit it is measured against. Many centres will then wait several months to see that the response holds before putting someone on the list, because a cancer that stays controlled is telling them something useful. These criteria only assess the cancer. How well your liver is working, and whether you are fit for major surgery, are judged separately.
Frequently asked questions
What are the Metroticket 2.0 criteria?#
The sum of the number of tumour nodules and the diameter of the largest in centimetres must not exceed a limit set by alpha-fetoprotein: 7 if AFP is under 200 ng/mL, 5 if AFP is 200–400, 4 if AFP is 400–1000, and no burden qualifies above 1000 ng/mL. Each band targets roughly 70% or better five-year hepatocellular-carcinoma-specific survival after transplantation.
How is the sum calculated?#
Number of nodules plus the diameter of the largest nodule in centimetres. Three nodules with a largest of 4 cm gives 7. It is not the sum of all the diameters — that is the most frequent arithmetic error, and it makes tumours look considerably worse than the rule intends.
What is the difference between the 2009 and 2018 versions?#
The 2009 up-to-seven rule used morphology alone and allowed a sum of 7 for everyone. Metroticket 2.0 keeps that limit only while AFP is under 200 ng/mL and tightens it as AFP rises. The newer version therefore both widens access for favourable biology and restricts it for unfavourable biology — it is not simply a more permissive rule.
Why does AFP above 1000 ng/mL exclude a patient entirely?#
Because at that level the biology outweighs the morphology. A markedly raised AFP predicts aggressive disease and post-transplant recurrence regardless of how small the tumour looks, and the model's calibration shows no tumour burden at which the survival target is still met. It is the clearest illustration of the model's premise, that anatomy alone is an incomplete description of a cancer.
Does being outside criteria rule out transplantation?#
Not necessarily. Downstaging with locoregional therapy is standard practice and works on both axes simultaneously — it reduces the tumour burden and frequently lowers AFP, which raises the limit that burden is measured against. Most protocols then require a period of stability before listing, because a sustained response carries prognostic information the numbers alone do not.
What does Metroticket assume without checking?#
The absence of macrovascular invasion and extrahepatic disease — both remain absolute contraindications and neither is assessed by the criteria. It also says nothing about hepatic reserve, performance status or comorbidity. Those are judged separately, with ALBI, Child-Pugh and MELD, and a within-criteria result is a statement about the tumour only.
Which version should be used in practice?#
Metroticket 2.0. The 2009 rule is retained here because a large body of published cohort data is expressed in its terms and needs to be read against it, but the 2018 revision is better calibrated and is what current allocation policies reference. Where the two disagree, act on the newer model.
Why is it called Metroticket?#
Because a metro fare rises with distance travelled. The 2009 analysis showed that survival after transplantation declines progressively with tumour burden rather than dropping abruptly at the Milan boundary, so the further a tumour is from Milan, the higher the price in expected outcome. Metroticket 2.0 extends the metaphor by letting alpha-fetoprotein set the fare rather than distance alone.
References
Original / primary reference
The original up-to-seven analysis
- Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10(1):35-43.
- Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis. N Engl J Med. 1996;334(11):693-700 (the Milan criteria).
Clinical practice guidelines
- Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236.