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Evolution of hepatocellular carcinoma in NAFLD: retrospective analysis of data from the multidisciplinary consultation meeting on liver tumors in Maine and Loire from 2007 to 2018

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Membres du jury

Monsieur le Professeur Paul CALÈS | Président Monsieur le Professeur Jérôme BOURSIER | Directeur Monsieur le Professeur François-Xavier CAROLI-BOSC | Membre

Monsieur le Docteur Frédéric OBERTI | Membre

Evolution of hepatocellular carcinoma in NAFLD: retrospective analysis of data from the multidisciplinary consultation meeting on liver tumors in Maine and Loire from 2007 to 2018

Évolution du carcinome hépatocellulaire sur NAFLD : analyse rétrospective des données de la réunion de concertation pluridisciplinaire des tumeurs du foie du Maine et Loire de 2007 à 2018

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ENGAGEMENT

DE NON PLAGIAT

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RE M E RC IE M E N TS

Je remercie le Professeur Paul Calès de me faire l’honneur de présider mon jury de thèse. Je vous remercie de vos conseils avisés pour mon parcours professionnel. Soyez assuré de mon profond respect et de ma reconnaissance.

Je remercie le Professeur Francois-Xavier Caroli-Bosc d’avoir accepté́ d’être membre de mon jury de thèse. Je vous remercie pour votre gentillesse et votre accueil chaleureux au sein de votre service. Soyez assuré de mon profond respect et de ma reconnaissance.

Je remercie le Professeur Jérôme Boursier d’avoir dirigé́ ce travail de thèse.

Je te remercie de m’avoir guidée tout au long de la construction de ce projet.

Je remercie le Docteur Frédéric Oberti d’avoir accepté́ d’être membre de mon jury de thèse. Je vous remercie de m’avoir enseigné l’Hépatologie, votre sens clinique sera un exemple pour ma pratique future.

Je remercie l’ensemble de l’équipe médicale de gastroentérologie du CHU d’Angers, pour m’avoir formé à cette belle spécialité́ tout au long de mon internat.

Je remercie également les équipes paramédicales du service de gastroentérologie du CHU d’Angers, pour leur bonne humeur au quotidien et pour avoir grandement contribué à ma formation professionnelle.

Je remercie l’équipe médicale du service de gastroentérologie du CH de Cholet, pour m’avoir accompagnée et suivie durant tout mon internat, ainsi que pour avoir participé́ à ma formation, notamment en endoscopie.

Je remercie l’équipe médicale de la réanimation du CH du Mans de m’avoir fait découvrir l’univers de la Réanimation et m’y avoir donné gout.

Je remercie l’équipe médicale de la réanimation du CHU d’Angers pour m’avoir conforté et soutenu dans mes choix.

Votre rigueur médicale, vos qualités humaines tant auprès des soignants et des patients font que c’est un vrai bonheur de travailler avec vous.

Je remercie le Professeur Alain Mercat, pour son accueil dans le service de réanimation médicale et dans l’enseignement du DESC, veuillez trouver ici l’expression de mes sincères remerciements.

Je remercie le Professeur Pierre Asfar, pour la transmission et le partage de son savoir scientifique et médical. Veuillez trouver ici l’expression de mon profond respect.

Je remercie le Docteur François Beloncle, de continuer à croire en moi pour la suite. Trouve ici l’expression de ma gratitude.

Je remercie mes différents chefs de cliniques et assistants les Docteurs Adrien Lannes, Derek Bardou, Mickael Landais, Floraine Zuberbulher, Pierre- Marie Fayolle, Tin-Hinan Mezdad pour les bons moments partagés et leur accompagnement tout au long de mon internat.

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RE M E RC IE M E N TS

À mes co-internes de promotion et amis, Charles et François, sans qui mon internat aurait été beaucoup moins joyeux.

À tous mes co-internes d’Hépato-gastro-entérologie, pour cette bonne ambiance de travail tout au long de ces 4 ans, pour votre humour décalé dans les instants les plus difficiles, et pour votre soutien dans les moments de joie comme dans les moments de doute.

À mes co-internes de la réanimation médicale du CHU d’Angers et mes co- internes de DESC, pour ce fantastique semestre.

Aux différents co-internes avec qui j’ai pu, à chaque semestre, faire un bout de chemin.

À ma fidèle amie depuis le collège, Claire.

Aux amitiés Angevines présentes depuis le début de l’externat, Aurélie, Marc, Shirley et Clément. Merci d’être là depuis maintenant 10 ans.

Aux amitiés créés aux fils des semestres de l’internat à Angers, Cholet ou au Mans : Julie, Romain, Sébastien, Lorine, Hélène, Isabelle, Eugénie, Christopher, Océane et tous les autres...

À Valérie et Joël, merci de m’avoir accueilli au sein de votre famille avec toute votre gentillesse. Ainsi qu’à Marie, Camille, Julie, et Charles, pour tous les bons moments partagés.

À mes grands-parents, oncles, tantes, et cousines, qui participent à mon équilibre.

À mes parents, qui me soutiennent sans relâche depuis près de 28 ans. Merci pour votre confiance indéfectible ainsi que votre affection qui ont fait de moi la personne que je suis aujourd’hui.

À mon frère, Paul, pour toutes tes petites attentions, ton humour, ta joie de vivre et tes encouragements.

Enfin, à Martin, pour ton soutien sans faille et ta patience à toute épreuve. À ces dernières années passées à tes côtés, et à toutes celles à venir…

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Liste des abréviations

AFP Alphafeatoprotein

BCLC Barcelona Clinic Liver Cancer HBV Hepatitis B Virus

HCC Hepatocellular carcinoma HCV Hepatitis C Virus

IARC International Agency for Research on Cancer NAFLD Non Alcoholic fatty liver disease

NASH Non Alcoholic steatohepatitis

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PLAN ABSTRACT INTRODUCTION

PATIENTS AND METHODS

1. Study population and design 2. Data collection

3. BCLC staging Classification and treatment schedule 4. Statistical analysis

RESULTS

1. All Patients

1.1. Presentation at a multidisciplinary consultation meeting on the last 10 years 1.2. Caracteristics

1.2.1. Malignant tumors’s caracteristics

1.2.2. Hepatocellular carcinoma’s caracteristics

2. Hepatocellular carcinoma in the patients with NAFLD 2.1. Presence or absence of cirrhosis

2.2. Diagnosis mode, discovery circumstance, treatment

2.3. Treatments proposed within BCLC stage in NAFLD patients 2.3.1. In cirrhotic patients

2.3.2. In non-cirrhotic patients DISCUSSION AND CONCLUSION BIBLIOGRAPHY

LIST OF FIGURES LIST OF TABLES TABLE OF CONTENTS

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Evolution of hepatocellular carcinoma in NAFLD: retrospective analysis of data from the multidisciplinary consultation meeting on liver tumors in Maine and Loire from 2007 to 2018

Hélène Julien 1 ; Frédéric Oberti 1,2, MD ; Isabelle Fouchard 1,2, MD ; Adrien Lannes1,2, MD ; Floraine Zuberbulher 1,2, MD ; Paul Calès 1,2, MD PhD ; Jérôme Boursier 1,2, MD PhD.

1 CHU Angers, Service d’Hépato-gastro-entérologie, Angers, France.

2 HIFIH Laboratory, UPRES 3859, SFR 4208, Bretagne Loire University, Angers, France

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ABSTRACT

Background and Aims : HCC commonly complicates chronic liver disease. NAFLD and

NASH are very common, more and more patients develop HCC despite the absence of cirrhosis.

Objectives : Using our multidisciplinary consultation meeting in Angers, we established

the epidemiology of HCC in Maine et Loire, then specifically analyzed patients with HCC on NAFLD. Then, we checked if the therapeutic management of patients was in compliance with the EASL 2018 guidelines.

Methods : Following our consultation meeting, we characterized the demographics of

HCC patients referred in the Maine et Loire between 2007 and 2018. All patients over 18 years of age who were presented at a liver tumour consultation meeting in our centre were included. Among the 2119 included patients, those with HCC on NAFLD were selected was extensively examined.

Results : 1440 patients (68%) had a malignant tumor, 30.5% of the tumors were benign and 1.5% unknown. 1203 patients were a diagnosis confirmed HCC. The majority of HCC occurred in patients with either underlying alcohol-induced cirrhosis (n=812;

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cirrhotic patients (p<0.001). 69 patients NAFLD were offered curative treatment (43.7%), 39.5% in cirrhotic patients versus 54.0% in non-cirrhotic patients (p=0.097).

In both cirrhotic and non-cirrhotic patients, two thirds of patients were offered treatment in accordance with the guidelines (98/158).

Conclusion : HCC on NAFLD represents nearly 13.1% of all HCC cases. Non-cirrhotic HCC-NAFLD is increasing in this population.

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INTRODUCTION

Hepatocellular carcinoma (HCC) is nowadays the second leading cause of cancer death worldwide (1). It is a major public health concern with one of the highest overall mortality compared to other cancers (2). It is also the most common primary hepatic malignancy in the world (3), with an increasing worldwide prevalence, with over 782,000 cases estimated to have occurred in 2012 according to the International Agency for Research on Cancer (IARC) (1,4). Therefore, there has been a significant increase in incidence over the last 20 years due to the increased incidence of viral cirrhosis C, probably of metabolic liver disease, and improving diagnostic possibilities. In France, the annual incidence of HCC was 12.1/100000 in men and 2.4/100000 in women in 2012 (5).

It occurs in the vast majority of cases on a liver that is already damaged by chronic liver disease, developed in 80% of cases on cirrhosis. However, more and more HCC are diagnosed on normal liver. In the Nzeoko’s study, 42.6% of HCC appeared on non- cirrhotic liver, and patients without cirrhosis survived longer than patients with cirrhosis.

The pathology, natural history, and prognosis of this tumor are significantly influenced by the presence or absence of cirrhosis in the non-neoplasic liver, and the presence of cirrhosis portends a poorer prognosis (6).

Nonalcoholic fatty liver disease (NAFLD) is a large spectrum of features that encompasses a spectrum of histological liver changes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with/without fibrosis, occurring in a dysmetabolic milieu (7),

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by 9% per year from 2004 to 2009 in the United States (10). More studies describe HCC in the setting of obesity and diabetes, two major risk factors for NAFLD (10–14). The increasing incidence of these conditions and the emerging evidence of HCC in non- cirrhotic NAFLD shows us the interest of diagnosing and managing them as soon as possible.

Unfortunately, it is a cancer with limited treatment options, aggressive nature and very low overall survival (8–10,12). In contrast to all other solid tumors, the therapeutic decision for HCC is not based on a prognostic classification. The TNM classification (tumor, node, metastasis) is not suitable because it does not take into account the severity of the underlying liver disease. Many other classifications have been proposed. The Barcelona Clinic Liver Cancer (BCLC) algorithm is the most widely used staging system(15). In practice, the therapeutic decision must be made in a multidisciplinary meeting according to three criteria: non-tumoral liver assessment, tumor extension assessment and general condition assessment. In theory, liver transplantation is the ideal treatment for cancer and cirrhosis simultaneously.

In the Dyson’s study, in 2000, less than 10% of Newcastle upon Tyne’s regional patients were referred to specialist services, increasing to over 85% by 2010 (16). It is important to involve all key professional groups in making clinical decisions for individual patients.

In the Taylor’s study, at least 90% of respondents agreed that effective team work results in improved clinical decision making, more coordinated patient care, improvement to overall quality of care, more evidence based treatment decisions, and improved treatment (17). Hence, importance of multidisciplinary consultation meetings that bring expertise.

In our University Hospital, in Angers, our pluridisciplinary meeting established since

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2007, allowed us to establish a database of patients with a probable HCC. This hospital served a stable population of about 800 000 people, and its weekly meeting was assisted by a clinical database that was retrospectively collected. The presence of associated liver disease was determined based on history, clinical, laboratory, radiological, histological and noninvasive screening tests. However, none has yet analyzed the prevalence outcome, the incidence of HCC as well as the evolution of our practices at Angers.

In the present work, we analyze the clinical presentation and histological diagnosis of all patients presented at a multidisciplinary meeting of liver tumors. Our first objective was to study the epidemiology of HCC in Maine and Loire.

In a second step, we specifically analyze patients with HCC on liver NAFLD and we compare them according to the therapeutic choices. Our second objective was to study the epidemiology of HCC on NALFD and to verify if the management is in accordance with the EASL 2018 guidelines.

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PATIENTS AND METHODS

1. Study population and design

In this retrospective observational study, we include all patients over the age of 18 who were presented at a multidisciplinary liver tumor meeting between January 1st, 2007 and April 1st, 2018 in the hepatogastroenterology department of the University Hospital Angers, France.

2. Data collection

First, we classified patients based on the data in the paper from the consultation meeting.

The data collected were as follows: tumor type (malignant / benign / undetermined), then malignant tumor type, and finally the etiology of chronic liver disease.

Patients were considered NAFLD when they met all the following criteria: no excessive alcohol consumption (20g / day in women, 30g / day in men) or other cause of chronic liver disease, overweight (BMI ≥ 25 kg/m2) and at least one of the following metabolic complication: diabetes, dyslipidemia, hypertension.

Secondly, for each patient with HCC on NAFLD, epidemiological and clinical data were recorded. The recorded data include: age, sex, etiology of chronic liver disease, circumstance of discovered HCC and non-invasive test.

The following radiological data were extracted from medical records: imaging type, size, location, presence of vascular invasion or metastases.

The following anathomopathological data were retained: histology in tumoral liver and in healthy liver.

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We collected treatments proposed. We then calculated the BCLC for each patient based on the available data.

3. BCLC staging Classification and treatment schedule

BCLC algorithm is the most widely used staging system (5–9). It includes prognostic variables related to tumour status, liver function and health performance status (Figure 1).

We focused our analysis on HCC on NAFLD group and we first analysed their BCLC stage.

We split our sections in 4 parts: Agreement with the Guidelines EASL 2018, “More aggressive” treatment compared to EASL Guidelines, “Less aggressive” treatment compared to EASL Guidelines, no treatment decision.

In addition, we split the BCLC A in 3 subgroups for more precision: BCLC A, 1 tumor <

5cm, BCLC A, 1 tumor > 5cm, BCLC A, 2 or 3 tumor < 3cm each one.

4. Statistical analysis

Quantitative and qualitative variables were expressed as mean ± standard deviation and percentages, respectively. Comparisons were performed using the Mann-Whitney test for quantitative variables and Fisher’s exact test for qualitative variables. Two-sided p-value of less <0.05 was considered statistically significant. Statistical analyses were performed using the SPSS version 18.0 software (IBM, Armonk, NY, USA).

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RESULTS

1. All Patients

1.1. Presentation at a multidisciplinary consultation meeting on the last 10 years

During the last decade, between January 1st, 2007 and April 1st, 2018, 2119 patients were presented at a disciplinary consultation meeting of liver tumors. The number of presentations at a multidisciplinary consultation meeting increased sharply in ten years:

from 96 in 2007 to 268 in 2017 (Figure 2). The participants were 63.8 years old (± 14.4 years); 69.3% were men (Table I). The number of referred cases of malignant tumors per year has increased steadily during this period, from 75 patients in 2007 to 160 patients in 2017. On average, malignant tumors accounted for 68% of the files submitted over the last 10 years, or 1440 files. While benign tumor accounted for 30.5% or 647 files at the same time, we are seeing an increase in the presentation of benign tumor cases, which represented 12.2% in 2007 compared to 44.1% of cases presented in 2017 (Figure 3).

1.2. Caracteristics

2119 patients were presented at a consultation meeting of liver tumors, among them 1440 (68%) had a malignant tumor. 30.5% of the tumors were benign and 1.5%

unknown (Figure 3). 1203 patients with a diagnosis of histologically or radiologically confirmed HCC were managed by the Hospital center of Angers (Figure 4). Among them, we find 158 patients with HCC on NAFLD (Figure 5).

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1.2.1. Malignant tumors’s caracteristics

Among 1440 malignant tumors, HCC was the most frequent and accounted for 83.5% of malignant tumor cases presented over the last 10 years (1203 cases), while cholangiocarcinomas accounted for 7.8% or 112 cases. The number of referred cases of HCC per year has increased steadily during this period, from 71 patients in 2007 to 126 patients in 2017. In Figure 3, results allow us to state that the number of malignant tumor cases has been increasing during the last 10 years; HCC is still the most prevalent condition each year and represents between 73.4 and 95.3% of the submitted cases.

Cholangiocarcinomas are therefore the second most represented malignant tumors but do not exceed 10.8% (in 2011) (Figure 4).

1.2.2. Hepatocellular carcinoma’s caracteristics

Analysis of the cohort revealed that in 67,5% of cases, HCC arose in patients with either underlying alcohol induced cirrhosis (n = 812), and 13.1% NAFLD (n = 158). It was referrals of HCC cases associated with NAFLD which rose the most dramatically. Indeed, in the space of 10 years, there has been a spectacular rise in the number of HCC on NAFLD in 2007, they represented 5.6% of the cohort compared to 23.8% (30/126). We therefore see an increase in cases of HCC in non-cirrhotic NAFLD liver over the past 10 years, although the number of cases is low. We have a growing increase in HCCs on NAFLD over the last 10 years to reach 26.3% of all HCCs in 2018. At the same time, we see a HCC number related to HCV decreasing from year to year (Figure 5).

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2. Hepatocellular carcinoma in the patients with NAFLD

2.1. Presence or absence of cirrhosis

Among the 158 patients with HCC on NAFLD, we find 86 cirrhotic patients (54.4%), 63 non-cirrhotic patients (39.9%), 9 undeterminate cirrhosis diagnose (5.7%). As shown in Figure 6, we did not observe any significant difference between groups in different years

according to cirrhosis status (p=0.644). The trend over the last 10 years shows us an overall stability in the number of HCC in healthy liver estimated at about 40%. There is therefore an increase in cases, but they remain proportional to whether or not there is a cirrhosis.

2.2. Diagnosis mode, discovery circumstance, treatment

There is no significant difference in the age of patients and in their sex between the cirrhotic and non-cirrhotic patient groups. On average, we found a population that was predominantly male (82.9%) and elderly (74 years old).

In Table I, HCC diagnosis is more frequently performed by an invasive liver biopsy method in the 158 patients (67.1%), while half of the HCCs were discovered incidentally (51.3%) in NAFLD patients.

We observe a more male at diagnosis in cirrhotic patients (p=0.048).

Concerning the diagnosis of cirrhosis, we note that in non-cirrhotic patients, the HCC diagnosis is made on 98.4% histology.

We observed a difference between cirrhotic and non-cirrhotic patients regarding the HCC discovery circumstance (p<0.001). In fact, HCC were predominantly fortuitously

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cirrhotic patients, the two main modes of discovery were fortuitous (65.1%), pain (23.8%). While in cirrhotic patients, the two main modes of discovery were fortuitous (37.2%), cirrhosis care (32.6%), then pain (10.5%), clinical complications (7%), hepatic biologic abnormalities (5.8%), follow-up of HCC (4.7%) and follow-up of hepatopathy (2.3%).

48 patients out of 158 patients (30.4%) are BCLC 0, A <5 cm or A 2-3 <3cm. A higher proportion of BCLC D is found in cirrhotic patients (24.4%), than non-cirrhotic patients (7.9%).

Finally, 69 patients out of 158 patients were offered curative treatment (43.7%), 39.5%

in cirrhotic patients versus 54.0% in non-cirrhotic patients (p=0.097). In cirrhotic patients, the main proposed treatment was endovascular treatment (24.4%) or palliative treatment and percutaneous ablation (23.3%), followed by comfort care (20.9%), surgery (12.8%). While in non-cirrhotic patients, the main treatment proposed was a curative treatment by surgery (46.0%), followed by endovascular treatment (14.3%), followed by sorafenib (12.7%), ablation percutaneous, radiolabelling and comfort care (7.9%) and endovascular treatment coupled with percutaneous ablation (1.6%).

2.3. Treatments proposed within BCLC stage in NAFLD patients

2.3.1. In cirrhotic patients

Among 86 cirrhotic patients, we performed treatment in accordance with the recommendations in 57 of the cases, or 66%.

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30 patients were classified as BCLC A, among them 13 were BCLC A 1 tumor < 5 cm.

11/13 (90%) received treatment in accordance with the recommendations. Among the 9 patients BCLC A 1 tumor > 5 cm, all have received treatment in accordance with EASL 2018 (100%). For the 8 patients classified in BCLC A 2 or 3 tumors < 3cm, 1 patient received more aggressive treatment, 1 patient did not have a treatment decision following the meeting, 3 patients had less aggressive treatments and 3 others had adequate treatment.

Among the 15 BCLC B, we were rather aggressive since 5 patients received more aggressive treatment, 2 less aggressive than the recommendations and 8 received adequate treatment.

Among the 12 BCLC C, we were very aggressive since 5 patients received more aggressive treatment, 2 less aggressive than the recommendations and 4 adequate treatments.

Among the 21 BCLC D, we were less aggressive since only 4 patients received more aggressive treatment than the recommendations and 14 patients received adequate treatment. 24% of cirrhotic patients (21/86) were classified BCLC D.

The majority of patients (66%) were offered treatment in accordance with the guidelines (57/86), 15/86 patients (17.4%) have a more aggressive treatment proposal and 10/86 (11.6%) have a less aggressive proposal than the guidelines (Table II).

2.3.2. In non-cirrhotic patients

Among 63 non-cirrhotic patients, we performed a more aggressive treatment, in 12 cases and a less aggressive treatment in 9 cases. The majority (41 patients) received treatment in accordance with the guidelines.

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2 patients were classified BCLC 0, allowing them to all receive treatment in accordance with the recommendations, mainly radiofrequency.

28 patients were classified as BCLC A, among them 14 were BCLC A 1 tumor < 5 cm.

13/14 (92%) received treatment in accordance with the recommendations. Among the 12 patients BCLC A 1 tumor > 5 cm, all have received treatment in accordance with EASL 2018 (100%). For the 2 patients classified in BCLC A 2 or 3 tumors < 3cm, 1 patient received less aggressive treatment and 1 patient had adequate treatment.

Among the 18 BCLC B, we were rather aggressive since 6 patients received more aggressive treatment, 4 less aggressive than the recommendations and 8 received adequate treatment.

Among the 10 BCLC C, we were very aggressive since 3 patients received more aggressive treatment, 3 less aggressive than the recommendations and 4 adequate treatments.

Among the 5 BCLC D, we were less aggressive since only 3 patients received more aggressive treatment than the recommendations, 1 patient did not have a treatment decision following the meeting and 1 patient received adequate treatment. 5% of non- cirrhotic patients (5/63) were classified as BCLC D.

The majority of patients (65%) were offered treatment in accordance with the guidelines (41/63), 12/63 patients (19%) have a more aggressive treatment proposal and 9/63 (14.5%) have a less aggressive proposal than the guidelines (Table III).

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DISCUSSION AND CONCLUSION

At present, there are limited reliable epidemiological data on the prevalence and incidence of NAFLD-related hepatocellular carcinoma, mainly because of the scarcity of population-based studies and the inability to identify NASH and NAFLD.

Our cohort shows a rapidly increasing proportion of HCC in patients with NAFLD. In 2017, 23.8% of HCCs were linked to a NAFLD versus 5,6% in 2007. In patients with HCC on NAFLD, a large part did not have underlying cirrhosis (39.9%).

The strengths of our work are: 1/ the large sample size of the study, 2/ the studied period over 10 years, 3/ the selection of patients, not with the ICD codes to infer the presence of NAFLD, but using manual chart reviews to verify the etiology of underlying liver disease including NAFLD.

The occurrence of HCC tripled in the last few decades in high income countries (from 1.4 per 100,000 subjects per year in 1975–1977 to 4.8 per 100,000 in 2005–2008), a rising incidence attributed mainly to the increasing role of NAFLD and NASH (18). In the past 10 years, many studies report more and more cases of HCC on NAFLD (19,20). Between 2000 and 2010, Dyson’s study revealed HCC related to NAFLD experienced the largest increase, accounting for 41 (35%) of the 118 cases (16). Our study is in agreement with the data in the literature. Interestingly, other previous studies (21,22) showed a relavely stable proportion of NAFLD-related HCC from 2005 to 2010, whereas we found a growing increase in HCC on NAFLD over the last 10 years to reach 26.3% of all HCC in 2018.

It has been reported that a significant number of patients with NAFLD-related HCC (more than one-third) have no extensive fibrosis at presentation (23). The overall rate of non- cirrhotic HCC on NAFLD in this study (39.9%) is slightly lower than reported rates. In the

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the absence of cirrhosis (24). Other studies have reported an even higher proportion of NAFLD-related HCC cases (10%–75%) that developed in the absence of cirrhosis (20).

In the Dyson study, HCC in patients with NAFLD occurred in 31 patients (23%) in the absence of histological or radiological characteristics of cirrhosis (16). In Yasui's study, the authors analyzed 87 cases of HCC in histologically confirmed steatohepatitis patients and found no cirrhosis established in 43 cases (49.4%) (19). In Mittal study, patients NAFLD or metabolic syndrome had more than a 5-fold risk to have HCC in the absence of cirrhosis, compared to patients with HCV. In this study, approximately 13% of patients with HCC do not appear to have cirrhosis. NAFLD and metabolic syndrome are the main risk factors of HCC in the absence of cirrhosis (21). In Piscaglia’s study, data also showed that almost 50% of cases HCC on NAFLD arose in the absence of frank cirrhosis (25). A recent study in 2019, shows that nearly 12% of HCC occur in patients without underlying cirrhosis in their cohort. NAFLD was the most common liver disease in these patients (26). In our cohort, the part of HCC in non-cirrhotic liver was at 39.9%. These results are therefore lower than those found in the literature. This observation is particularly worrying because it indicates that the development of HCC could complicate hepatic steatosis with fibrose alone.

In the Gawrick’s study (26), HCC in non-cirrhotic liver were discovered mainly by chance or pain. Similarly, in our study, HCC in non-cirrhotic patients were discovered by chance or pain. This seems appropriate in that no follow-up could be done in these patients who did not participate in the screening, and therefore have HCC discovered on a larger clinical

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study (27). We were able to observe a significant proportion of curative treatment proposals in our cohort (43.7%), We did not find any significant difference between cirrhotic and non-cirrhotic patients (p=0.097). In non-cirrhotic patients, curative treatment by surgery was the most frequent, as in the Romero study (28). It would appear that non-cirrhotic patients have more advanced tumours than cirrhotic patients but still see more curative treatment. Having a non-cirrhotic liver therefore probably allows us to be more aggressive in our treatment proposals.

With regard to the BCLC stages, we were able to observe that our cohort of patients, regardless of the BCLC stage, had received treatments in accordance with the 2018 recommendations. We found more BCLC D in cirrhotic patients, probably, because when cirrhotics have HCC they decompensate their cirrhosis and no longer have a liver function preserved.

However, this study has several limitations. As with any retrospective study, some data points were missing despite our individual patient's chart review. In addition, we have taken the opportunity to compare our treatment proposals with the 2018 guidelines, however the majority (148/158 patients) were submitted before 2018.

In conclusion, HCC in NAFLD represents nearly 13.1% of all HCC cases in this French monocentric study. Non-cirrhotic HCC-NAFLD is increasing in this population. A future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the timeliest and effective treatment.

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LIST OF FIGURES

Figure 1 : BCLC staging system and treatment startegy (from the EASL guidelines) ... 1

Figure 2 : Number of cases presented annually ... 2

Figure 3 : Types of tumors presented per year ... 3

Figure 4 : Nature of malignant lesions by years ... 4

Figure 5 : Etiologies of chronic liver disease associated with HCC in % ... 5

Figure 6 : Presence of absence cirrhosis in NAFLD patients group reaches HCC in % ... 6

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Figure 2 : Number of cases presented annually

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Figure 6 : Presence of absence cirrhosis in NAFLD patients group reaches HCC in %

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LIST OF TABLES

Table I : Circumstance of discovered, BCLC and treatement within NAFLD group ... 1 Table II : Proposal of the meeting reunion according to the BCLC in NAFLD cirrhotic .... 2 Table III : Proposal of the meeting reunion according to the BCLC in NAFLD non cirrhotic ... 3

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Table I : Circumstance of discovered, BCLC and treatement within NAFLD group

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Table II : Proposal of the meeting reunion according to the BCLC in NAFLD cirrhotic

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Table III : Proposal of the meeting reunion according to the BCLC in NAFLD non cirrhotic

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TABLE OF CONTENTS

ABSTRACT ... 2

INTRODUCTION ... 4

PATIENTS AND METHODS ... 7

1. Study population and design ... 7

2. Data collection ... 7

3. BCLC staging Classification and treatment schedule ... 8

4. Statistical analysis ... 8

RESULTS ... 9

1. All Patients ... 9

1.1. Presentation at a multidisciplinary consultation meeting on the last 10 years .. 9

1.2. Caracteristics ... 9

1.2.1. Malignant tumors’s caracteristics ... 10

1.2.2. Hepatocellular carcinoma’s caracteristics ... 10

2. Hepatocellular carcinoma in the patients with NAFLD ... 11

2.1. Presence or absence of cirrhosis ... 11

2.2. Diagnosis mode, discovery circumstance, treatment ... 11

2.3. Treatments proposed within BCLC stage in NAFLD patients ... 12

2.3.1. In cirrhotic patients ... 12

2.3.2. In non-cirrhotic patients ... 13

DISCUSSION AND CONCLUSION ... 15

BIBLIOGRAPHY ... 18

LIST OF FIGURES ... 21

LIST OF TABLES ... 1

TABLE OF CONTENTS ... 1

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JULIEN Hélène

Évolution du carcinome hépatocellulaire sur NAFLD : analyse rétrospective des données de la réunion de concertation

pluridisciplinaire des tumeurs du foie du Maine et Loire de 2007 à 2018

Mots-clés : carcinome hépatocellulaire, stéatose hépatique dysmétabolique, épidémiologie

Evolution of hepatocellular carcinoma in NAFLD: retrospective analysis of data from the multidisciplinary consultation meeting on liver tumors

in Maine and Loire from 2007 to 2018

R É SU M É A B ST R A C T

Methods :

Results :

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