MD Pietro Addeo

MD Manuela Cesaretti

MD Rodolphe Anty

MD Antonio Iannelli

Liver transplantation for bariatric surgery-related liver failure: a systematic review of a rare condition

Keywords: bariatric surgery, liver transplantation, liver failure, malabsorption, biliopancreatic diversion. Highlights

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Bariatric surgery (BS) has been largely proven to be the most effective, safe and durable treatment of morbid obesity and its related comorbidities [START_REF] Mingrone | Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial[END_REF][START_REF] English | American Society for Metabolic and Bariatric Surgery estimation of metabolic and bariatric procedures performed in the United States in 2016[END_REF] . Due to obesity pandemic, non-alcoholic fatty liver disease (NAFLD)-related liver failure is becoming increasingly reported as indication for liver transplantation [START_REF] Doycheva | Nonalcoholic Steatohepatitis is the Most Rapidly Increasing Indication for Liver Transplantation in Young Adults in the United States[END_REF] . Surgery-induced weight loss is associated with resolution of hepatic complications of obesity and avoids progression toward chronic liver failure [START_REF] Lassailly | Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients[END_REF][START_REF] Mattar | Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome[END_REF][START_REF] Younossi | Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)[END_REF] . The increasing popularity of bariatric surgery over the recent years has led to a heightened awareness of specific complications associated with each bariatric procedure. These complications might include, although rare, acute and chronic liver failure (LF), which were first reported as potentially life-threatening complications of jejuno-ileal bypass (JIB) [START_REF] Burke | Liver transplantation for cirrhosis following jejuno-ileal bypass--regional cytokine differences associated with pathological changes in the transplant liver[END_REF] . Protein malnutrition and bacterial overgrowth-both occurring mainly after metabolic operations with a prevalent highly malabsorptive component have been thought to be responsible of initiating and/or precipitating liver lesions of non-alcoholic fatty liver disease (NAFLD) in patients with JIB [START_REF] Markowitz | Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management[END_REF] . Jejuno-ileal bypass has been progressively abandoned because it is associated with several life-threatening complications including LF [START_REF] Hocking | Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases[END_REF][START_REF] Ravitch | The price of weight loss by jejunoileal shunt[END_REF] .

Non-alcoholic fatty liver disease is a common obesity-related comorbidity characterized by a variable rate of regression after BS [START_REF] Lassailly | Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients[END_REF] . BS represents the safest method to interrupt the progression of NAFLD toward steatohepatitis and/or cirrhosis and lead to remission of steatohepatitis in morbidly obese patients [START_REF] Lassailly | Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients[END_REF][START_REF] Caiazzo | Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study[END_REF][START_REF] Schneck | Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis[END_REF] . However, for poorly understood reasons BS, can trigger LF in some morbidly obese patients [START_REF] Cazzo | Liver failure following biliopancreatic diversions: a narrative review[END_REF] . In fact, acute and/or chronic LF have been ,although rarely,reported following several bariatric procedures including long-limb Roux-en-Y gastric bypass (LLRYGB) [START_REF] Cotler | Hepatic decompensation after gastric bypass surgery for severe obesity[END_REF] and biliopancreatic diversion (BPD) with duodenal switch (DS) [START_REF] Baltasar | Liver failure and transplantation after duodenal switch[END_REF] or according to Scopinaro [START_REF] D'albuquerque | Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery[END_REF] . While some patients presenting with LF after BS may evolve toward complete resolution after appropriate medical treatment and eventual reversal of the bariatric procedure, others progress toward end-stage liver disease requiring liver transplantation (LT). In the era in which chronic end-stage liver disease resulting from NAFLD represents a growing indication for LT [START_REF] Doycheva | Nonalcoholic Steatohepatitis is the Most Rapidly Increasing Indication for Liver Transplantation in Young Adults in the United States[END_REF] and BS is emerging as a promising means against the epidemic of obesity-related liver complications [START_REF] Lassailly | Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients[END_REF][START_REF] Younossi | Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)[END_REF] , the role and the results of LT for BS-related LF remain rarely reported [START_REF] Cazzo | Liver failure following biliopancreatic diversions: a narrative review[END_REF] . Here, we systematically review the literature regarding indications, timing, and results of LT for BS-related LF, which remains an extremely rare complication of BS.

Methods

Search Strategy

The EMBASE, MEDLINE, and COCHRANE central databases were systematically searched from inception up through December 2017 for articles describing LT for LF after BS. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and limited to manuscripts written in English. The following phrases were used as search MESH terms: "bariatric surgery," "jejunoileal bypass," "gastric bypass," and "biliopancreatic diversion." Each phrase was combined with "liver transplantation," "liver failure," "acute liver failure," or "end-stage liver disease."

Article Selection and Data Extraction

Potentially eligible articles were screened by two independent investigators (PA, AI). The exclusion criteria included articles describing: 1) LF after BS resolving after medical treatment and/or surgical reversal of BS procedure that did not necessitate LT; 2) LF after BS leading to the patient's death in the absence of LT; 3) LT in patients with previous BS due to acute LF (ALF) or chronic LF (CLF) unrelated to BS (e.g., toxic intake, alcohol abuse, viral etiology); 4) studies lacking data of patients.

Discrepancies between the two investigators were resolved via consensus. The full texts of the selected articles were analyzed for eligibility. The authors of the articles were contacted when additional information was needed. The primary outcomes of this review were indications, morbidity, and mortality of LT for BS-related LF. A secondary outcome was the reversal rate of BS after LT. Data regarding the study period, number of patients, the type of BS performed, the time elapsed between the BS and the onset of LF, patients characteristics at BS and LT, surgical complications, morbidity and mortality of LT and presence and timing of reversal of BS were extracted from the included articles. All of the data were extracted using a standardized extraction form.

Statistical Analysis

The methodological limitations and the volume of incomplete data hampered the use of metanalysis. Continuous data were expressed as mean ± standard deviation (SD) and range and the median and range, as appropriate. Categorical variables were presented as numbers and percentages. Differences between groups were assessed using the chi-squared or Fisher's exact test (categorical variables) and the Wilcoxon rank sum test or the Student's t-test (continuous variables).

This review is largely descriptive because of the small simple size.

Results

The attrition diagram is shown in Figure 1. The initial search resulted in 564 studies. Only 14 studies matched the inclusion criteria, however. These studies included a total of 36 patients listed, of which 32 finally underwent LT [START_REF] Burke | Liver transplantation for cirrhosis following jejuno-ileal bypass--regional cytokine differences associated with pathological changes in the transplant liver[END_REF][START_REF] Markowitz | Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management[END_REF][START_REF] Baltasar | Liver failure and transplantation after duodenal switch[END_REF][START_REF] D'albuquerque | Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery[END_REF][START_REF] Lowell | Liver transplantation after jejunoileal bypass for morbid obesity[END_REF][START_REF] Souza-Gburek | Liver transplantation for jejunoileal bypass-associated cirrhosis: allograft histology in the setting of an intact bypassed limb[END_REF][START_REF] Castillo | Liver transplantation in a case of steatohepatitis and subacute hepatic failure after biliopancreatic diversion for morbid obesity[END_REF][START_REF] Kelley | Change in oral absorption of tacrolimus in a liver transplant recipient after reversal of jejunoileal bypass: case report[END_REF][START_REF] Geerts | The multicenter Belgian survey on liver transplantation for hepatocellular failure after bariatric surgery[END_REF][START_REF] Auclair | Successful orthotopic liver transplantation after biliopancreatic diversion with duodenal switch[END_REF][START_REF] Sgambato | Liver failure in an obese middle-aged woman after biliointestinal bypass[END_REF][START_REF] Ralki | Liver failure after long-limb gastric bypass[END_REF][START_REF] Silva | Acute liver failure secondary to bariatric surgery: An indication for liver transplantation[END_REF][START_REF] Eilenberg | Significant Liver-Related Morbidity After Bariatric Surgery and Its Reversal-a Case Series[END_REF] . The number of patients reported by each study and the percentage of patients transplanted are reported in Table 1. Most of these studies were case reports (8/14) and reported patients from the United States (15/36), Europe (18/36), Brazil (3/36), and Canada (1/36). There were four reports published before the year 2000 and 10 published thereafter; only three studies reported more than five patients. Overall, 14 cases were described before the year 2000 and 22 thereafter.

Patient characteristics

There were 36 patients listed for LT. This cohort had a median age of 44 years (range: 19-63 years) and a Female/Male ratio of 4. The type of previously performed BSs included JIB in 16 (44.4%) patients, BPD according to Scopinaro (distal gastrectomy with a long (100-200cm) Roux-en-Y gastric bypass) (n=14) or with DS (75% longitudinal gastrectomy, preservation of the pylorus, creation of an alimentary limb approximately 50% of total small bowel length, and a common channel length of 100 cm )(n=3) in 17 patients (47.2%), and bilio-intestinal bypass (n=1) (2.8%), LLRYGB (n=1) (2.8%), and a single-anastomosis omega-GBP (n=1) (2.8%) (Table 2). The median Body Mass Index (BMI) of the patients at the time of BS was 46 kg/m 2 (range: 33-85.2 kg/m 2 ) and median weight loss after BS was 51 kg (range: 27-93 kg). During the index BS, only 4 patients (11.1%) had received a liver biopsy, which revealed steatosis in 3 patients and non-alcoholic steatohepatitis (NASH) in 1 patient. All of the patients had signs of LF developing a median of 20 months after BS (mean: 105 months; range: 5-300 months). This interval of time was significantly shorter after BPD than JIB (mean ± SD, 22±21 months (range: 6-84 months) vs 269±27 (range: 228-330 months); p=0.0001). It was not possible to correlate the mean interval of time elapsed from BS to LF with the mean weight loss associated with the two procedures because of a lack of data. Among patients who underwent BPD with the Scopinaro procedure, the interval of time from BS to LF was 24±22 months (median: 14 months; range: 7-84 months). In patients who received the DS the interval of time from BS to LF was 11±6 months (median: 8 months; range: 6-20 months). All of the patients were listed for LT; four died (11.1%) while on the waiting list. The median time spent on the waiting list until LT was 60 days (range: 2-260 days). When comparing the outcomes before and after the year 2000, as expected, the number of LTs performed for LF after JIB significantly decreased from 100% to 9% (p=0.0001). This reflects the fact that JIB was largely abandoned by 2000.

LT outcomes

Four deaths (4/32; 12.5%) were reported after LT. Three deaths in the early postoperative course were due to pulmonary infection (1), multi-organ failure (1), and bleeding and sepsis (1). One patient died six years after LT of lung carcinoma. Morbidity was reported in 8 cases (25%). Two patients underwent liver retransplantations, one for an acute Budd-Chiari syndrome and one for a NASH-related recurrent cirrhosis occurring 10 months after the first LT. Twenty-one patients (65.5%) had their BS procedure reversed, one (4.8%) before LT, 15 (71.4%) during LT, and five (23.8%) after LT. The BS reversal involved JIB for 9 patients, BPD for 11 patients, and biliointestinal bypass for 1 patient. Histology of the explanted livers, rarely reported, is detailed in Table 3. Biopsy-proven steatosis recurrence in the postoperative period was reported in six (18.7%) patients, four of whom did not experience BS reversal after LT. One of these patients developed recurrent NASH-related cirrhosis shortly after LT that led to retransplantation.

Discussion

The current systematic review indicates that severe LF after BS is an extremely rare condition which in some cases required liver transplantation. The few cases reported in the literature underline: 1) the low incidence of LF after BS; 2) the safety of BS in presence of hepatic complications of obesity [START_REF] English | American Society for Metabolic and Bariatric Surgery estimation of metabolic and bariatric procedures performed in the United States in 2016[END_REF] . In fact, BS remains the most effective and safe treatment for hepatic complications of obesity, which can spare so many obese patients from these potentially lethal complications [START_REF] Lassailly | Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients[END_REF][START_REF] Mattar | Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome[END_REF] . However, the epidemic of obesity and NASH with the consequent increase in the prevalence of BS motivates the need for widespread knowledge of LF after this kind of surgery among physicians. Even if rare, the occurrence of severe LF should be known and patients developing LF should be addressed promptly to tertiary center.

The mechanism of LF in the context of BS remains poorly understood but several hypotheses have been formulated. First, the presence of a bypassed intestinal segment may result in protein malnutrition and deprivation of hepatotropic factors reaching the liver [START_REF] Markowitz | Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management[END_REF][START_REF] Lowell | Liver transplantation after jejunoileal bypass for morbid obesity[END_REF] . Second, the exclusion of a long jejuno-ileal segment of intestine can lead to injury of the mucosal barrier, which may in turn facilitate the absorption into the portal system of inflammatory cytokines arising from intestinal bacterial overgrowth [START_REF] Geerts | The multicenter Belgian survey on liver transplantation for hepatocellular failure after bariatric surgery[END_REF] . Of note is the fact that LF has been reported only after bariatric procedures including an intestinal bypass; this complication has never been described in patients undergoing metabolic operations with a prevalent restrictive component. Furthermore, the longer the intestinal bypass the higher the risk of LF because of bacterial overgrowth and malnutrition. Third, morbidly obese patients frequently harbor NAFLD lesions, which might, in the presence of acute malnutrition following BS, rapidly progress toward acute LF [START_REF] Markowitz | Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management[END_REF][START_REF] Cazzo | Liver failure following biliopancreatic diversions: a narrative review[END_REF] . The timing and mechanisms leading to LF are not fully understood and appear to differ among the patient records collected for this systematic review. In fact, histological analysis of the explanted livers, which was available in only 11 cases, revealed acute necrosis and steatosis in six patients and cirrhosis in the remaining five patients.

These findings may favor the hypothesis of acute hepatitis-like kinetics in most cases [START_REF] D'albuquerque | Liver transplantation for subacute hepatocellular failure due to massive steatohepatitis after bariatric surgery[END_REF] and chronic liver disease in others [START_REF] Souza-Gburek | Liver transplantation for jejunoileal bypass-associated cirrhosis: allograft histology in the setting of an intact bypassed limb[END_REF] . One may speculate that the systematic performance of a liver biopsy in the setting of BS may make it possible to partially clarify the mechanism leading to LF after BS. Liver biopsy at the time of BS could be done systematically to investigate the effect of BS on liver complications [START_REF] Verna | Liver biopsy at the time of bariatric surgery: a benefit for patients and the medical community[END_REF] , which was the case for only four patients in the present review. However, the systematic performance of liver biopsy appears difficult to propose because of the inherent potential risk for patients.

We have shown that the occurrence of LF is more common after particular bariatric procedures. No LF related to metabolic operations with a prevalent restrictive component such as gastric band, vertical gastroplasty and sleeve gastrectomy has been reported thus far despite the large number of such procedures performed worldwide. Most of cases of LF needing LT were reported after JIB and BPD mainly according to Scopinaro than with DS. All of these procedures are characterized by varying amounts of malabsorption due to a short common channel and a long biliopancreatic limb for BPD or the exclusion of a very long segment of intestine for the JIB. Finally, only two cases were reported after distal Roux-en-Y gastric bypass (RYGBP), which includes a short common channel as a BPD and single anastomosis omega in the other. Indeed, the classical RYGBP anatomy includes a short biliopancreatic (generally less than 50 cm) and alimentary (between 75 and 150 cm) and is mainly considered to be a restrictive procedure. The short length of the intestinal bypass may therefore have a protective effect against the occurrence of LF. In the case of a distal bypass there is not only a long intestinal bypass but the restrictive component of the procedure is also extreme because the gastric pouch has a capacity of 30-50 ml [START_REF] Hammer | Medical complications of bariatric surgery: focus on malabsorption and dumping syndrome[END_REF] . The association of an extreme restriction and a long intestinal malabsorptive bypass may lead to protein malnutrition due to the reduced capacity to eat coupled with reduced absorption [START_REF] Brolin | Long-limb gastric bypass in the superobese. A prospective randomized study[END_REF] . In one patient, the gastric bypass was a single anastomosis omega gastric bypass, which has been shown to result in complications such as malnutrition and deficiencies and weight loss that are more similar to those reported for BPD than for standard RYGBP [START_REF] Lee | Laparoscopic Roux-en-Y versus mini-gastric bypass for the treatment of morbid obesity: a prospective randomized controlled clinical trial[END_REF] . However, the degree of malabsorption and restriction depend on the volume of the gastric pouch and the biliopancreatic limb, which may vary in length.

The elapsed time from BS to LF appears to also significantly differ according to the type of BS. In the current review, LF occurred sooner after BPD according to Scopinaro and DS compared with JIB. It may be argued that a BPD according to Scopinaro, compared with JIB, includes a restrictive distal gastrectomy and a very short common alimentary limb of 50 cm in the original description of the technique, which could induce a rapid malnutrition state that rapidly leads to LF. The anatomy of the BPD with DS is less extreme because the restrictive component is the sleeve gastrectomy and the length of the common channel is generally one meter, which is double that described for the BPD according to Scopinaro [START_REF] Marceau | Biliopancreatic diversion with duodenal switch[END_REF] . Although these differences may account for the rarity of LF occurring after BPD with DS compared with the Scopinaro procedure, this hypothesis remains speculative because previous studies did not determine the occurrence of LF after BPD according to Scopinaro in large cohorts. Indeed, Scopinaro et al. did not find any case of LF in 2241 patients undergoing a BPD [START_REF] Scopinaro | Biliopancreatic diversion[END_REF] . In addition, Giannini et al. showed that preexisting liver lesions of NAFLD were not exacerbated by the performance of BPD in obese patients [START_REF] Giannini | Long-Term Follow-Up Study of Liver-Related Outcome After Bilio-Pancreatic Diversion in Patients with Initial, Significant Liver Damage[END_REF] . However, it must be stressed that these studies lacked paired liver biopsies performed before or at the time of BPD.

The rates of morbidity and mortality of LT for BS-related LF are largely comparable with those of LT performed for other indications [START_REF] Agopian | Evaluation of Early Allograft Function Using the Liver Graft Assessment Following Transplantation Risk Score Model[END_REF] . Furthermore, the presence of previous BS appears to not be associated with specific complications. Because LF has been linked to BS in the series reviewed, reversal of the bariatric procedure was performed in more than half of the cases simultaneously with LT. Reversal, which was not associated with a higher rate of mortality, consisted of lengthening the common alimentary limb with no bowel leak or obstruction reported.

During the follow-up period, recurrent steatosis was noted in six patients, four of whom had not had BS reversal. This finding underlines the necessity of BS reversal synchronously or in a delayed fashion to reduce the risk of recurrence of LF. Geerts et al. suggested that BS reversal occur either synchronously or early in the postoperative LT course to avoid recurrent LF [START_REF] Geerts | The multicenter Belgian survey on liver transplantation for hepatocellular failure after bariatric surgery[END_REF] . However, reversal may be technically challenging in the setting of malnutrition because of the risk of anastomotic complications or even impossible in the case of a distal gastrectomy (e.g., in the case of BPD according to Scopinaro or the sleeve gastrectomy in the BPD with DS). In these cases, only the intestinal bypass component should be revised increasing the length of the common channel. The exact timing of delayed BS reversal could be not determined in the present review because one patient for whom BS reversal was postponed during the 8 th postoperative week developed recurrent cirrhosis shortly after LT and needed retransplantation. The same patient had recurrent steatohepatitis requiring two more liver retransplantations and died after the third recurrence [START_REF] Lefere | Refractory subacute steatohepatitis after biliopancreatic diversion[END_REF] . This case highlights the need for an intensive follow-up after LT in patients not undergoing synchronous BS reversal and the fact that the mechanism of acute steatohepatitis progressing toward LF is not yet fully known. It should also be argued that the reversal of a bariatric procedure ineluctably leads to the recurrence of obesity, which may in turn lead to NAFLD in the graft [START_REF] Bhati | Long-term Outcomes in Patients Undergoing Liver Transplantation for Nonalcoholic Steatohepatitis-Related Cirrhosis[END_REF] .

The present review is characterized by several limitations such as the small number of studies eligible for analysis, which may be a source of bias. Half of the included patients had a JIB, a technique that has been virtually abandoned for many years and is of no interest in current clinical practice. Additionally, patients experiencing LF after BS who did not require LT or died before being evaluated for a LT or patients for whom medical treatment alone successfully reversed LF were not captured in the analysis. However, it was more likely that most cases of LF resolving without LT and not causing death of the patients were not even reported in the literature. National and International surveying through registries could certainly contribute to define the exact incidence and outcomes of LF after bariatric surgery.

Conclusions

Bariatric surgery-related LF represents an extremely rare indication for LT most often performed after JIB and BPD. Morbidity and mortality after LT for such an indication are comparable to other indications, even when the BS reversal is performed simultaneously.

Table 1 :

 1 Selected studies reporting liver transplantation for bariatric surgery-related liver failure.

Table 2 :

 2 Preoperative characteristics of patients undergoing liver transplantation for bariatric surgery-related liver failure.

Table 3 :

 3 Postoperative outcomes for liver transplantation for bariatric surgery-related liver failure. surgery; BMI= Body Mass Index; NAFLD= Nonalcoholic fatty liver disease; JIB=jejunoileal bypass; BPD= biliopancreatic diversion; BPD-DS: biliopancreatic diversion with duodenal switch; BI-BP= biliointestinal bypass; LL-GBP=distal gastric bypass; OMEGAGBP=one-anastomosis gastric bypass; NASH=non-alcoholic steatohepatitis; 1= BMI expressed as Kg/m 2

	38 40 37 42 41 33 38 35 BS=Bariatric 35 Auclair M Canada 1 2013 Sgambato D Italy 1 2013 Baltasar A Spain 2 2014 Ralki M Belgium 1 2016 Rodriguez Silva C Spain 1 2016 Eilenberg M Austria 1 2017 -	F F F F F F F F M -	BPD BPD BPD BPD-DS BI-BP BPD-DS BPD-DS D-GBP BPD OMEGAGBP	45 40 47 54 54 58 49 39.5 -33	-------Yes -Yes	-------Yes/Steatosis -NASH	25 22 25 30 -39 -22.9 18 -	45 53 50 -70 --36 --	20 21 14 8 8 6 20 7 12 5

Table 3 :

 3 Postoperative outcomes of LT for bariatric surgery-related liver failure

	Author	N=	Time	Waiting	MELD at	Mortality	Mortality	Morbidity	Reversal	Timing of BS	Histology
			of	list	listing	while	after OLT	after OLT	of BSP	reversal	of the explanted
			OLT			waiting					liver
			after			OLT
			BSP
			(mo)
	Burke GW		300	-	-	-	-	-	Yes	3 months	NA
										after OLT
	Lowell JA		288
			228
			252
			300

Acknowledgements

The authors would like to thank Professor Anja Geerts (Ghent University Hospital, Belgium) and Professor Mohamed Ilias Mohamed Safwan (Henry Ford University Hospital, Detroit,

Conflicts of Interest and Disclosures: None

Michigan, USA) for providing additional information regarding their articles.

Funding: No funding.


Henri Lorphelin

Lauranne Rossard

Carina Rua

Flavie Arbion

Philippe Bougnoux

Gilles Body

Lobna Ouldamer
email: l.ouldamer@chu-tours.fr

Evolution of characteristics of women with endometrial cancer during a 40 years study period

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Endometrial cancer (EC) is the first gynaecological cancer affecting women in western countries with 382.069 new cases and 89.929 worldwide in 2018 (1)[START_REF] Amant | Endometrial cancer[END_REF][START_REF]Cancers gynécologiques -Recommandations et outils d'aide à la pratique[END_REF][START_REF] Arnold | Recent trends in incidence of five common cancers in 26 European countries since 1988: Analysis of the European Cancer Observatory[END_REF]. In France, 6852 new cases and 2148 specific deaths occurred in 2012 versus 8360 new cases and 2340 specific deaths in 2017 [START_REF] Bray | Geographic and temporal variations in cancer of the corpus uteri: incidence and mortality in pre-and postmenopausal women in Europe[END_REF][START_REF] Weiderpass | Trends in corpus uteri cancer mortality in member states of the European Union[END_REF][START_REF]WHO Mortality Database[END_REF][START_REF] Boll | Increased incidence and improved survival in endometrioid endometrial cancer diagnosed since 1989 in The Netherlands: a population based study[END_REF][START_REF] Duncan | Cancer of the body of the uterus: Trends in mortality and incidence in England, 1985-2008[END_REF][START_REF] Galaal | Adjuvant chemotherapy for advanced endometrial cancer[END_REF][START_REF] Binder-Foucard | Cancer incidence and mortality in France over the 1980-2012 period: solid tumors[END_REF][START_REF] Chen | Survival of endometrial cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage[END_REF]. A growing incidence was noticed in France with 68 per 100.000 in 1989-1993 moving to 75 per 100.000 in 2005-2010 [START_REF] Bray | Global incidence statistics 2018: GLOBOCAN: estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF].

Most ECs are diagnosed at early stages (75% stage I) with generally only surgery as therapeutic management conferring an image of a "good prognosis" cancer with a 5-year overall survival of 81% for all stages combined [START_REF] Bray | Global incidence statistics 2018: GLOBOCAN: estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF][START_REF] Key | The dose-effect relationship between « unopposed » oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk[END_REF][START_REF] Allen | Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition[END_REF][START_REF] Jenabi | The effect of body mass index on endometrial cancer: a meta-analysis[END_REF][START_REF] Kaaks | Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review[END_REF][START_REF] Friberg | Diabetes mellitus and risk of endometrial cancer: a meta-analysis[END_REF][START_REF] Esposito | Metabolic syndrome and endometrial cancer: a meta-analysis[END_REF][START_REF] Kempers | Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study[END_REF][START_REF] Ferenczy | Histology of the human endometrium: From birth to senescence[END_REF]. However, it is well known that EC is a heterogeneous entity with various histological types. ECs are broadly classified into two major types based upon clinicopathologic features: 1) Type I ECs are low grade endometrioid ECs (International Federation of Gynecology and Obstetrics (FIGO) grades 1 end 2) which comprise the majority of all ECs (70-80% of cases), almost present at an early stage, and have a good prognosis [START_REF] Key | The dose-effect relationship between « unopposed » oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk[END_REF][START_REF] Allen | Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition[END_REF][START_REF] Jenabi | The effect of body mass index on endometrial cancer: a meta-analysis[END_REF][START_REF] Kaaks | Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review[END_REF][START_REF] Friberg | Diabetes mellitus and risk of endometrial cancer: a meta-analysis[END_REF][START_REF] Esposito | Metabolic syndrome and endometrial cancer: a meta-analysis[END_REF][START_REF] Kempers | Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study[END_REF][START_REF] Ferenczy | Histology of the human endometrium: From birth to senescence[END_REF](22), 2) Type II ECs include FIGO grade 3 endometrioid ECs and the nonendometroid histologies: serous (10% of cases), clear cell (<5% of cases), mixed cell, undifferenciated and carcinosarcomas (or malignant mixed mullerian tumors<5% of cases).

They are high grade and have a poor prognosis, even though surgery and adjuvant treatments permitted the reduction of locoregional recurrence rate (22)[START_REF]Serous Endometrial Cancers That Mimic Endometrioid Adenocarc[END_REF][START_REF] Mendivil | Non-endometrioid adenocarcinoma of the uterine corpus: A review of selected histological subtypes[END_REF][START_REF] Tropé | Clear-cell and papillary serous cancer: Treatment options[END_REF][START_REF] Goto | Prognosis of high-grade endometrial cancer: a comparison of serous-type and clear cell type to grade 3 endometrioid-type[END_REF][START_REF] Prat | FIGO staging for uterine sarcomas[END_REF][START_REF] Pacaut | Uterine and ovary carcinosarcomas: outcome, prognosis factors, and adjuvant therapy[END_REF][START_REF] Boll | Incidence and survival trends of uncommon corpus uteri malignancies in the Netherlands, 1989-2008[END_REF]. They seem to occur in a different population than the one concerned by endometrioid ECs: type I ECs are stimulated by estrogen and are associated with prolonged exposure to endogenous or exogenous estrogen unopposed by progesterone, causing continuous proliferation of the endometrium, then endometrial hyperplasia and subsequent carcinoma. Typically, type II ECs are not estrogen sensitive and often occur in the presence of an atrophic endometrium [START_REF] Key | The dose-effect relationship between « unopposed » oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk[END_REF][START_REF] Allen | Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition[END_REF][START_REF] Jenabi | The effect of body mass index on endometrial cancer: a meta-analysis[END_REF][START_REF] Kaaks | Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review[END_REF][START_REF] Friberg | Diabetes mellitus and risk of endometrial cancer: a meta-analysis[END_REF][START_REF] Esposito | Metabolic syndrome and endometrial cancer: a meta-analysis[END_REF][START_REF] Kempers | Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study[END_REF][START_REF] Ferenczy | Histology of the human endometrium: From birth to senescence[END_REF](22).

What we propose in the present work is to study modifications in patient's characteristics, histological types and their impact on overall survival among patients with endometrial cancer managed in our institution through the last four decades.

Patients and methods:

Women referred for endometrial cancer at the tertiary oncological referral center of Tours (France) were prospectively entered into a multidisciplinary team meeting register between October 1975 and June 2014. With the authorization of the institutional review board we retrospectively reviewed this prospective database.

Inclusion criteria were: women with EC managed between October 1975 and June 2014 with available histological data. Exclusion criteria were: women with uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma or adenosarcoma).

Individual records of all patients were reviewed and analysed from the medical records held by our institution on a computerized database. Variables included patient demographics, histological and survival data. Patients with known Body Mass Index (BMI) were categorized as: underweight (BMI < 18,5 kg/m 2 ), normal (18,5 ≤ BMI ≤ 24,9 kg/m 2 ), overweight (25 ≤ BMI ≤ 29,9 kg/m 2 ) and obese (BMI ≥ 30 kg/m 2 ).

In the first part of "results" section, patient's age, BMI, were treated as continuous variables.

Survival data were extracted from medical files when available, if not, the birthplace (city hall) of each patient was contacted to consult survival data of the birth registry. The date of death was noted on the marginal notes on the birth certificate. In the absence of a marginal mention of death, the patient was considered alive.

In the absence of a mentioned birthplace, the residence city hall or departmental archives made it possible to find survival data. Overall survival (OS) was calculated.

As stated in the introduction, ECs are classified into two major types based upon clinicopathologic features. Bokhman in 1983, [START_REF] Bokhman | Two types of endometrial carcinoma[END_REF] was the first who hypothesized that there are two types of ECs driven by different metabolic and endocrine signals: type I being more common, consisting of endometrioid, low grade, diploid, hormone-receptor positive tumors that are moderately-or well-differentiated and more common in obese women. Type II ECs are more common in non-obese women, of non-endometrioid histology, high grade, aneuploidy, poorly differentiated, hormone receptor negative and associated with higher risk of metastasis and poor prognosis. This historical system has been useful but overlap between type 1 and 2 is now well recognized.

For numeric data, results are reported as mean and median values ± standard deviation (SD). The Fischer exact and χ² chi-square tests were used to compare categorical values.

Characteristics of women and tumors were analyzed using Chi-square statistics or Fisher's exact test for categorical variables and t-test or analysis of variance (ANOVA) for continuous variables. Values of P<0.05 were considered to denote significant differences. Data were managed with an Excel database (Microsoft, Redmond, WA, USA) and analyzed using the R 3.0.2 software, available online. For the survival analysis, survival curves were generated (in months) using the method of kaplan-meier, based on the interval from the date of diagnosis to the date of last contact or death from any cause. The log-rank test was used to compare differences between survival curves.

RESULTS

From 1 th October 1975 to 30 th June 2014, 842 women were managed for an endometrial cancer in the university teaching hospital of Tours. Mean age at diagnosis was 64.7 years ± 10.6 (range: 27-93). Table 1, report characteristics according to the decade of management. There was a significant difference in age at diagnosis; women diagnosed after 2000 were significantly older than women diagnosed in other decades (p<0.0001). There was no difference in parity (p=0.46), with 15.5 % of nulliparous women during the study period. There was no difference in age at diagnosis between women having type I EC and women having type II EC(64.32 vs 65.95 years, p=0.15). Histological repartition changed during the study period (Figure 1). Proportion of histological type II increased with a factor of 3 in 40 years (p<0.0001), representing more than 1 cancer on four in the 2000s versus less than 10% in the 1970s.

The increase of histological type II proportion was not traduced by a difference in overall survival according to the decade of diagnosis (p=0.16) Figure 2.

There was a significant difference in overall survival according to histological subtype p=0.0002 (Figure 3). Women with normal weight had better overall survival than other BMI categories (Figure 4).

We performed two-by-two comparison confirming these findings:

Normal weight/underweight (p<0.001)

Normal weight/obese (p=0.002)

Normal weight/overweight (p=0.002)

There we no statistical difference when we compared OS of obese women to women with overweight (p=0.52)

We also found a significant statistical difference when we compared OS of underweight women to obese women (p<0.0001) and to overweight woman (p<0.0001)

DISCUSSION

The rising incidence of EC in western countries these last decades is thought in literature to be due to an augmentation in the incidence of endometrioid EC. The augmentation in type II EC proportion was more important in our population, with 9.2 % in the 1970s to 27.9 % in the 2000s. Our study period concerned 40 years that permitted a global view of evolving tendencies of minority histological subtypes. The augmentation was marked in the 1980s. During that decade, advances in immunochemistry and molecular biology contributed to a more precise and specific detection of tumours, particularly for type II EC. On another hand the university hospital centre of Tours was identified as a tertiary referral in the late 1970's that might partially explain the high incidence of type II EC. There was no real evolution of the gynaecological surgery team or neither in the modalities of patient's recruitments nor in the administrative region

The comparison with literature data is more delicate because of adjunction of grade 3 endometrioid EC to type II EC during the study period, because they are considered as having similar prognosis [START_REF] Ueda | Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths[END_REF][START_REF] Brinton | Etiologic heterogeneity in endometrial cancer: Evidence from a Gynecologic Oncology Group trial[END_REF]. When performing our analyses, grade 3 endometrioid EC was included in type II ECs as reported in the latest recommendations.

Despite emergence of more aggressive histological subtypes, overall survival remained stable whatever the decade of management. Boll et al found a significant rise in 5-year overall survival for type I EC from 83 % in 1990 to 85 % in 2007 (p<0.001) [START_REF] Boll | Increased incidence and improved survival in endometrioid endometrial cancer diagnosed since 1989 in The Netherlands: a population based study[END_REF], and in parallel a diminution in 5-year overall survival from 15 to 18 % for type II EC [START_REF] Boll | Incidence and survival trends of uncommon corpus uteri malignancies in the Netherlands, 1989-2008[END_REF].

In the present study we did not found any difference between age at diagnosis between women with type I EC and women having type II EC (64.32 vs 65.95 years, p=0.15), but when considering the whole population, women diagnosed in the 2000s were significantly older than the others (p<0.0001). This is in line with the majority of published studies. For type I EC, the incidence increases for women aged ≥60 years at diagnosis (p<0.001) (8). [START_REF] Park | Impact of body mass index on the prognosis of Korean women with endometrioid adenocarcinoma of the uterus: A cohort study[END_REF]. Other studies showed the same results when comparing survival of obese EC patients to non obese patients [START_REF] Canlorbe | Severe Obesity Impacts Recurrence-Free Survival of Women with High-Risk Endometrial Cancer: Results of a French Multicenter Study[END_REF].

We found poorer overall survival in underweight women with EC when compared to women with other BMI categories. Cachexia and sarcopenia are clinical entities, which negatively impact on the outcome of cancer patients. The international consensus conference defined cancer cachexia as a multifactorial syndrome characterized by an ongoing loss of squeletic muscle with or without fat mass that cannot be fully reversed by conventional nutritional support [START_REF] Fearon | Definition and classification of cancer cachexia: an international consensus[END_REF]. The weight loss is associated with muscle wasting or sarcopenia that occurs across all weight groups, including those of normal, overweight and obesity. In terms of prognosis, the use of BMI along with weight loss is a very powerful predictor for overall survival in patient with advanced cancer whatever the type [START_REF] Von Haehling | Cachexia as a major underestimated and unmet medical need: facts and numbers[END_REF].

CONCLUSION

An analysis on a larger population of underweight women with EC is needed to identify specific factors. A trend to develop more type II EC can partly explain these results. We identified a clear trend of augmentation of type II EC, known to have a poor prognosis while necessitating specific surgical management. Histologic analysis standardisation, surgical strategy and amelioration of adjuvant treatments permitted to maintain a stable overall survival for the whole population despite this augmentation.

Table 1 -Characteristics of the whole population.

 1

	Characteristics	1970s	1980s		1990s	2000s	p
	(n=842)	n=76	n=315		n=139	n=312
	Age (years)	63.7±8.6 [46-84]	62.9 [27-87]	±9.9	62.6 ±9.6 [39-85]	67.5 ±8.6 [28-93]	<0.0001
	BMI (kg/m 2 )	27.1±8.1 [13-62.5]	26.1±5.5 [15.6-48.5]	26.8±6.1 [17.1-47]	29.3±7.9 [14-71]	<0.0001

Table 2 -Population characteristics according to BMI category.

 2

		Underweight	Normal	Overweight	Obese	p
	1970s	7 (14%)	16 (32%)	10 (20%)	17 (34%)	<0.0001
	(n = 50)
	1980s	7 (2.6%)	118 (44%)	95 (35.4%)	48 (18%)
	(n = 268)
	1990s	3 (2.2%)	59 (44.4%)	33 (24.8%)	38 (28.6%)
	(n = 133)
	2000s	13 (4.7%)	78 (28.1%)	72 (26%)	114 (41.2%)
	(n = 277)
	Type I	22 (3.8%)	216 (37.4%) 169 (29.2%) 171 (29.6%)	0.83
	(n=578/674)
	Type II	8 (5.3%)	55 (36.7%)	41 (27.3%)	46 (30.7%)
	(n=150/167)
	Type I/II in the	Type I: 6	Type I: 15	Type I: 8	Type I: 15
	1970s	(85.7%)	(93.7%)	(80%)	(88.2%)
		Type II: 1	Type II: 1	Type II: 2	Type II: 2
		(14.3%)	(6.3%)	(20%)	(11.8%)
	Type I/II in the	Type I: 7	Type I: 100	Type I: 85	Type I: 42
	1980s	(100%)	(84.7%)	(89.5%)	(87.5%)
		Type II: 0	Type II: 18	Type II: 10	Type II: 6
		(0%)	(15.3%)	(10.5%)	(12.5%)
	Type I/II in the	Type I: 1	Type I: 46	Type I: 24	Type I: 32
	1990s	(33.3%)	(77.9%)	(72.7%)	(84.2%)
		Type II: 2	Type II: 13	Type II: 9	Type II: 6
		(66.7%)	(22.1%)	(27.3%)	(15.8%)
	Type I/II in the	Type I: 8	Type I: 55	Type I: 52	Type I: 82
	2000s	(61.5%)	(70.5%)	(72.2%)	(71.9%)

  Boll et al, found an augmentation in the incidence of types I ECs. In a study with 32.332 ECs of which 80 % were of endometrioïd type[START_REF] Boll | Increased incidence and improved survival in endometrioid endometrial cancer diagnosed since 1989 in The Netherlands: a population based study[END_REF]. They also found in 3618 women with type II EC a diminution in the incidence between 1989 and 2008 (30 versus 13 per 100.000). This corresponded to a diminution in the incidence of serous histological subtype (68 % of type II EC) from 22 to 7.1 per 100.000, clear cells ECs incidence was stable[START_REF] Boll | Incidence and survival trends of uncommon corpus uteri malignancies in the Netherlands, 1989-2008[END_REF].

	Between 1994 and 2006, Evans
	et al found in a study concerning 6867 EC patients, an augmentation in type I EC incidence
	(12.0 versus 16.3 for 100.000, p<0.001). The incidence of type II EC was considered stable
	(2.5 versus 2.2 for 100.000) (32-33). Duong et al, confirmed these results in a study with 145
	922 type I and 15 591 type II ECs (34).

An analysis of 48.150 patients extracted from the SEER database (Surveillance, Epidemiology, and End Results) between 1988 and 2001, found a proportion of 83.7% of type I EC. Rates of type II ECs progressed over time with 14.7 % in the 1990s to 17.3 % in the 2000s (p<0.001). Serous histological subtype increased from 5.8 % to 6.7 %

[START_REF] Ueda | Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths[END_REF]

.

  2 in BMI confers 1.6-fold higher risk of developing a type I EC when compared to women with normal BMI. In Europe, it is thought that weight excess is responsible of the occurrence of 60% of new cases of EC[START_REF] Renehan | Incident cancer burden attributable to excess body mass index in 30 European countries[END_REF].

	Duncan et al, found a constant augmentation in incidence for women aged 60-64 years from 44.8 to 72.8 per 100.000 between 1985 and 2008. The incidence diminished for women aged less than 55 years, with a new rise in the 2000s (9). We also found that BMI were higher in the 2000s when compared to BMIs of other decades of diagnosis (p<0.0001). French population count 15 % of obese and 32.3 % of overweight persons (37). Obese women represented 41.1% of the whole study population; this report is lower than American women affected by EC. Kamal et al found a mean BMI of 34.3 kg /m 2 and a proportion of 46.8% for obese women treated for a type I EC (38). Our results are similar to previous French reports (39). The proportion of type II EC diminished with the augmentation of BMI. Literature report the same pattern for type I EC with less aggressive histological features associated with the augmentation of BMI (myometrial invasion and LVSI) (40). The augmentation of BMI is largely associated to EC risk. Lindermann et al, showed that EC risk raised linearly with BMI. In comparison with women with normal BMI, relative risk of developing an EC was 6.36 (95%CI; 3.08-13.16) when BMI≥ 40 kg /m 2 and 0.53 (95%CI ; 0.19-1.47) when BMI < 20 kg/m 2 (41). In another study on 1 036 877 women in Norway, overweight and obese women, in comparison to women with normal BMI, had a relative risk of 1.36 (95%CI: 1.29-1.42) and of 2.51 (95%CI: 2.83-2.66) (42). Each augmentation of 5 al, reported an augmentation in specific cancer mortality for women with BMI≥ 35 kg/m 2 (HR=3.00, 95%CI 1.59-5.67) (45). In the ASTEC population study (44), Crosbie et al, did not found any influence of BMI category on overall and disease free survival (40). This was in line with Park's results who showed no difference in survival when comparing women with kg/m The effect of BMI on survival of EC patients still a matter of debate in literature (44). Arem et BMI < 25 kg/m 2 to those with BMI ≥ 25 kg/m 2

Figure legends: