Differences between radiology and

histopathology: Are we judging correctly?Simona Onali1, Emmanuel Tsochatzis1, James

O’Beirne1, Aileen Marshall1, TuVihn Luong2, Massimo Pinzani1,

Pinelopi Manousou1

1The Royal Free Sheila Sherlock Liver Unit, Royal Free Hospital and UCL Institute for Liver and Digestive Health, London, UK

2Department of Cellular Pathology, UCL Medical School, Royal Free Campus, London, UK

BackgroundSelection criteria for OLT in patients with HCC are based on radiological assessment of the number and size of tumours

Retrospective studies about HCC patients undergoing LT reported different grade of discordance between radiological and histological findings1-4.

Factors other than tumour size and number may affect post-LT outcomes :

Pre-transplant aFP level >1000 ng/ml associated with higher risk of HCC recurrence even among patients transplanted within Milan criteria5

1Sotiropoulos 2005 Transplantation2Grasso 2006 Transplantation3Shah 2006 Transplantation4Chen 2009 HPB5 Hameed 2014 Liver transplantation

Aims of the study

1. To analyse any discrepancies between radiological reports and histopathological findings in the explant of patients undergoing LT for HCC

2. To identify potential factors that could predict HCC recurrence and survival post-LT between the parameters available during the pre-operative assessment period.

Patients and Methods

All consecutive patients who underwent LT for HCC between January 1997 and February 2014 at the Royal Free Hospital

Retrospectively:

- Demographic and clinical data (sex, age, aetiology of liver disease, date of LT, pre-LT HCC treatment, aFP levels)

- Pre-LT radiological findings (HCC number and size, macrovascular invasion, lymph-nodes invasion)

- Histopathological findings on explant (HCC number and size, differentiation, micro/macrovascular invasion)

- Donor characteristics

- Immunosuppression type and levels

- HCC recurrence and HCC-related death

Patients and Methods

Discrepancy between radiological and histopathological findings was assessed comparing:number of nodulessize of biggest nodule fulfilment of Milan/UCSF criteria

Patients were considered underestimated if:-nodule number and/or size was bigger on explant compared to imaging-they did not fulfil selection criteria on explant (in discordance to radiology)

They were considered overestimated when the opposite occurred.

Results: baseline patients’

characheristics (n=185)

Age median, range 55 (27-68) Gender male 150 (81%)

Aetiology

- HCV- HBV - ALD- Autoimmune - NAFLD- Other

101 (54%) 35 (19%) 28 (15%)

9 (5%) 7 (4%) 5 (3%)

LT period

- 1996-2000- 2001-2005- 2006-2010- 2011-2014

46 (25%)38 (20%)59 (32%)42 (23%)

Pre-LT HCCtreatment

- Total- TAE/TACE- RFA- Ethanol injection- Resection- Combination

126 (68%)107

5 3 1

10

Pre-LT a-FP level (IU/L)

median, range- >1000 - 100-1000- < 100

12.1 (2-7936)5 (3%)

25 (14%)152 (83%)

Results: pre-LT imaging

Results:histopatholog

ical findings

Radiology Histology

O inside Milan O outside Milan

O inside Milan O outside Milan

Discrepancy in selection criteria

Classification according to Milan criteriaPathology

Within Outside

Radiology within 132/185 (71%) 40/185(22%)

outside 4/185 (2%) 9/185 (5%)

Classification according to UCSF criteriaPathology

Within Outside

Radiology within 150/185 (81%) 28/185(15%)

outside 2/185 (1%) 5/185 (3%)

40/172 (23%) patients fell outside MC due to : number of HCC 10/40 size of HCC 20/40 both 10/40

28/178 (16%) patients fell outside UCSF criteria due to: number of HCC 19/28 size of HCC 5/28 both 4/28

Discrepancy between radiological and histological findings

Number of nodules: 104/185 (56%) 78 underestimated

- 60 pts -> 1-2 nodules - 18 pts -> 3-4 nodules

26 overestimated by 1-2 nodules - 10 treated between imaging and LT

Size of biggest nodule: 158/182 (87%) 93 underestimated

- 44 pts -> difference ≥ 10 mm

65 overestimated- 25 pts -> difference ≥ 10mm

Results: HCC recurrence post-LT29/185 (15.6%) developed HCC recurrence after a median of 37m post LT (4-157)

16 (55%) -> liver 13 (45%) -> metastatic disease involving lungs, bones or lymph

nodes

20/29 died after a median of 48 m post-LT (7-157)

16/29 (55%) outside Milan criteria according to explant14/29 (48%) underestimated by imaging

- size of biggest HCC (n=10)- n. of nodules and size of biggest (n=4)

Vs 13/29 (45%) inside Milan criteria according to explant

3/29 (10%) had aFP >1000 IU/l

-> vs 2/153 (1.3%) in non recurrence patients

13/29 (45%) had aFP >100 IU/l

-> vs 17/153(11%) in non recurrence patients

Results: predictors of HCC recurrence post- LT

In Cox regression factors significantly associated were:

1.aFP levelsp=0.001, OR=4.1, 95% CI=2.00 - 8.5

2. Radiological size of biggest nodule p=0.001, OR=1.04, 95% CI=1.02 - 1.06

Number of nodules p=0.6

What about the number of nodules?

Cut-off ?

Cut-off ?

aFP cut-off= 100 IU/l

Sensitivity 41% Specificity 89%

Cut-off of biggest nodule size = 3 cm

Sensivity 62%Specificity 74%

…what if we combine aFP <100 IU/l and size of biggest nodule <3 cm ?

AUROC=0.72,

p=0.0001,

95% CI=0.62-0.82

Sensitivity=77%

Specificity= 70%

We then compared our cut-offs with those proposed in the

literature

Total number of patients Recurrence HCC

aFP (IU/l)

<100 152 (83%) 16 (55%)

100 - 1000 25 (14%) 10 (35%)

>1000 5 (3%) 3 (10%)

Size of biggest nodule (cm)

<3 117 (76%) 11 (38%)

>3 36 (24%) 18 (62%)

Kaplan Meier for HCC recurrence according to aFP and size of biggest

HCC cut-offs

aFP<100 and diam<3cm

aFP>1000 and diam>3cm

aFP<100 and diam>3cm

aFP 100-1000 and diam<3cm

aFP 100-1000 and diam>3cmLog rank p<0.001

Results: Survival post-LT

49/185 (27%) patients died after a mean of 42 months (6-160)

post-LT

HCC related 1-year survival 98%, 5-year survival 91%

Overall related 1-year survival 95%, 5-year survival 80%

Cause of death:•HCC recurrence (41%)

- median follow-up 40 months (7-157)- 1-year survival 89%- 5-year survival 53%

•de-novo malignancy (15%)•decompensated cirrhosis (14%) •sepsis (10%)•chronic rejection (4%) •Unknown, but not HCC-related (16%)

Results: predictors of HCC-related mortality post-LT

Cox regression: pre-LT factors significantly associated:

1. aFP levels >100kU/lp<0.001, OR=5.1, 95% CI=2-12.7

2. Radiological size of biggest HCCp=0.021, OR=1.04, 95% CI=1.01-1.08

Conclusions

1. Discordance between radiological and histological findings.

tumour progression between imaging and LT (tumour biology, waiting time)

innacurate imaging staging ?

Does it really matter?

Recurrence occured in 35% of underestimated patients (vs 10% of the rest) according to Milan Criteria

4 (2%) overestimated according Milan criteria: how many patients we are overestimating and not listing ?

Conclusions

2. aFP and radiological diameter of the biggest HCC were the only pre-LT factors significantly associated with HCC recurrence and HCC related survival.

• A lower aFP cut-off of 100 IU/l showed higher sensitivity than the current in identifying HCC recurrence post LT

• Combination of aFP <100 Ku/l and size of biggest HCC <30 mm seems to perform better than the actual selection criteria.

• We do propose to consider patients with diameter>30mm for LT when aFP <100 IU/L.