2019/2020
Francisca José Lopes Barbosa
Impacto da Cirurgia Metabólica na
Prevenção de Cancro / Impact of
Metabolic Surgery on Cancer
Prevention
Mestrado Integrado em Medicina Área: Cirurgia Geral /Medicina Clínica Tipologia: Monografia Trabalho efetuado sob a Orientação de: Doutora Laura Elisabete Ribeiro Barbosa E sob a Coorientação de: Prof. Dr. João Araújo Teixeira Trabalho organizado de acordo com as normas da revista:
Edorium Jornal of Gastroenterology Surgery Francisca José Lopes Barbosa
Impacto da Cirurgia Metabólica na
Prevenção de Cancro/ Impact of
Metabolic Surgery in Cancer
Prevention
UC Dissertação/Projeto (6º Ano) - DECLARAÇÃO DE INTEGRIDADE
Eu, Francisca José Lopes Barbosa, abaixo assinado, nº mecanográfico 201405583, estudante do 6º ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboração deste projeto de opção.
Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão, assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica.
Faculdade de Medicina da Universidade do Porto, 10/03/2020
Assinatura conforme cartão de identificação:
UC Dissertação/Projeto (6º Ano) – DECLARAÇÃO DE REPRODUÇÃO
NOME
Francisca José Lopes Barbosa
NÚMERO DE ESTUDANTE E-MAIL
201405583 franciscabarbosa1996@gmail.com
DESIGNAÇÃO DA ÁREA DO PROJECTO Cirurgia Geral
TÍTULO MONOGRAFIA
Impacto da Cirurgia Metabólica na Prevenção de Cancro / Impact of Metabolic Surgery on Cancer Prevention
ORIENTADOR
Dra. Laura Elisabete Ribeiro Barbosa
COORIENTADOR
Professor Dr. João Araújo Pereira
ASSINALE APENAS UMA DAS OPÇÕES:
É AUTORIZADA A REPRODUÇÃO INTEGRAL DESTE TRABALHO APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE.
É AUTORIZADA A REPRODUÇÃO PARCIAL DESTE TRABALHO (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE.
DE ACORDO COM A LEGISLAÇÃO EM VIGOR, (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) NÃO É PERMITIDA A REPRODUÇÃO DE QUALQUER PARTE DESTE TRABALHO.
Faculdade de Medicina da Universidade do Porto, 10/03/2020
Assinatura conforme cartão de identificação: ______________________________________________ x
Aos meus pais, pelo esforço de uma vida para que este percurso fosse o mais tranquilo possível. Palavras não chegam para mostrar a minha gratidão. Obrigada pelo apoio incondicional.
À minha tia, por todas as rezas e mensagens de boa sorte.
Ao meu namorado, pelos 6 anos de (tentativa de) transmissão da sua calma. Aos meus amigos, por tornarem este caminho mais feliz e por me fazerem sentir em casa.
TYPE OF ARTICLE: Review Article
TITLE: Impact of Metabolic Surgery in Cancer Prevention
AUTHORS: Francisca Barbosa1, João Araújo2, Laura Elisabete Barbosa3
AFFILIATIONS:
1 Francisca Barbosa, Faculty of Medicine, Porto University, Oporto, Portugal,
franciscabarbosa1996@gmail.com
2 João Araújo Teixeira, Graduated Assistant of Surgery, Department of General
Surgery, Centro Hospitalar de São João, Oporto, Portugal, jpat@med.up.pt
3 Laura Elisabete Barbosa, Graduated Assistant of Surgery, Director of General
Surgery, Department of General Surgery, Centro Hospitalar de São João, Oporto, Portugal, elisabete_barbosa17@hotmail.com
CORRESPONDING AUTHOR DETAILS
Francisca Barbosa
Alameda Prof. Hernâni Monteiro, Porto, Portugal
franciscabarbosa1996@gmail.com
Short Running Title: Metabolic Surgery and Cancer Prevention
Guarantor of Submission: The corresponding author is the guarantor of
submission.
ABSTRACT
Obesity and its related complications represent a huge burden is today’s medical practice and have a great impact in the mean life expectancy. Obese individuals have an increased risk of cancer and the mechanisms linked to this risk have been study for years so that a physiopathology base can be established. Metabolic surgery is a recent concept that integrates the systemic alterations that happen after surgery induced weight loss and that can possibly revert the increased cancer risk associated with obesity. This paper reviews the main mechanisms linked with the increased cancer risks in these individuals and how metabolic surgery can help preventing them.
This study is narrative review based on PubMed/MEDLINE literature search. In a first-stage search, 1312 results were obtained and after careful reading and selection, a total number of 64 articles were included in this review including also a references research.
Metabolic surgery is associated with a decrease in the overall cancer risk, all-cause mortality and cancer-related mortality in obese individuals. Apart from the great amount of weight loss, there is also a reduction in the low-grade chronic inflammation, in circulating levels of estrogen, insulin and consequent insulin-like growth factor-1, all of which have been proved to have mitogenic proprieties. This type of surgery is associated with an undoubtable risk reduction of hormone-related cancers such as endometrium and breast cancers and also linked with a decrease number in pancreatic and liver cancers cases. The relation between surgery and gastrointestinal cancers is not so fully understood and the results are
not unanimous. The anatomical gastrointestinal alterations may be implicated in some cases of colorectal cancer after surgery.
Keywords: Metabolic surgery, bariatric surgery, obesity, cancer
INTRODUCTION
The incidence of overweight and obesity continues to rise and alongside them, the associated comorbidities such as hypertension, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) and multiple solid cancers [1-8]. All together they represent a huge burden to medical practice [7], and it’s responsible for a great amount of all medical costs worldwide, reflecting the importance of the effort to control it and minimize unfavorable outcomes. A lot of work has been put into research on how to minimize the impact of this disease in the mean life expectancy, that is reduced by 5-10 years in these individuals [9, 10].
There are numerous mechanisms linked with increased cancer risk by obesity, including the chronic state of inflammation, insulin resistance [11, 12], increased oxidative stress [2], changes in gut microbiome, dysregulation of adipose tissue with adverse interaction between various adipokines and steroid hormones [2, 7, 13-17].
The increase overall solid cancer risk in obese patients is well established, particularly gastrointestinal cancers such as colorectal [11, 18-20], esophageal, pancreatic [21, 22], liver [6, 23] and also hormone-related cancers like breast [24, 25], endometrium [16, 25-30] and prostate cancer [31]. These types of cancer are examples of what is called “obesity-related cancers”. Evidence suggest that this risk can be attenuated with surgery [5, 7, 8, 32-34]. In the UK, 5,5% of all cancers were attributed to excess body weight [35] (meaning body mass index (BMI) ³ 25 kg/m2), similar to the percentage found in Canada [36]. However, there
metabolic surgery and is actually increase by it (mostly for colorectal [18, 31] and esophageal cancers [37]).
Numerous studies have shown that bariatric surgery is the most effective and sustainable way to reduce both risk and incidence of those comorbidities [2, 8, 10, 19, 25, 31, 34, 38]. Surgery has already been proved to have major beneficial associations with several clinical outcomes, with reductions in risk seen for T2DM, hypertension, angina, myocardium ischemia and obstructive sleep apnea. Resolution of T2DM and hypertension was also been seen [5]. When compared with other interventions like lifestyle changes with reduce caloric intake and increase exercise, obesity surgery proved to be superior not only in the amount of weight loss but mostly in its maintenance [39]. As the overall cancer risk reduction after surgery was strongly correlated with the amount of weight loss [32], this intervention is thought to be excellent to reduce the solid cancer risk. However, bariatric surgery acts not only by decreasing the BMI but also by metabolic changes as decreased insulin resistance, reduction in angiogenic and growth factors and also decrease in the chronic inflammatory state, all of them implicated in the association between increased body fat and cancer [2]. In fact, these associated metabolic changes that seem to occur after the various types of bariatric surgery demonstrated to be more relevant in risk reduction than the decrease in BMI and therefore the name “metabolic surgery”.
This study focuses on resuming the several types of cancer related to obesity, what mechanisms are involved and what changes after metabolic surgery.
METHODS
This study is a narrative review based on PubMed/MEDLINE literature search in September 2019 using the terms "bariatric surgery”, "metabolic surgery", "sleeve gastrectomy”, "gastric bypass", "obesity surgery” and also "cancer", "tumor" “malignancy” and finally “neoplasm”, as it reunites the several terms used to refer to this subject. There were obtained 1312 results from this first search. Case reports, conference papers, letters to authors and narrative reviews were not included. Furthermore, due to time and resources limitation, articles with paid access to the full text and articles written in languages other than English or Portuguese were not included. After the first phase selection (title and abstract reading), 52 articles were left. When integral reading was complete, 8 additional texts were excluded, leaving a final number of 44 articles to be included in this literature view. A research on the references of the included articles was also conducted, obtaining 20 more articles, leaving a total number of 64 articles included.
RESULTS
Overall cancer risk
Several studies have suggested an overall reduced risk of cancer in obese patients following bariatric surgery relative to obese individuals who do not undergo bariatric surgery [4, 7, 8, 32, 33] and that the positive effect of bariatric surgery on neoplasic outcomes seems more noticeable for women when compared to men. Also, the connection between surgery and cancer risk is not fully understood but is thought to be the consequence of metabolic variabilities linked to obesity that are reestablished by persistent weight loss, or by surgically-stimulated caloric restriction, and / or bypass of a fully hormonal and active intestine [7, 8, 10, 33].
A study conducted by Schauer et al. [32] found that cancer risk after bariatric surgery appeared to be closely associated with the amount of weight loss achieved at one year and those that lost the greatest amount of weight had the lowest cancer incidence. In the group having bariatric surgery, weight loss not only reduced the risk of overall cancer but surprisingly, it also reduced the risk among the subgroup of non-obesity associated cancers. For patients having bariatric surgery, for each 10% of weight loss there was an 14% reduction in cancer risk. As the mean weight loss for an average bariatric patient was about 27% of their initial weight at 1 year, the reduction in cancer risk was 34% and when comparing with obese matches who did not underwent bariatric surgery, estimated weight loss was around 1% at one year and was not associated with
any change in cancer risk. The results in Hunsinger’s [3] studies were in concordance with these.
Adams et. al. [8] performed an analysis in cancer incidence between the two groups that showed that reduction in incidence appeared to be greatest for obesity-related cancer, whereas the mortality reduction was equally great for obesity-related cancers and non-obesity-related cancers, all suggesting that the weight loss associated with gastric bypass (GB) surgery may reduce the development of new cancers likely related to obesity.
Not only bariatric surgery can be a way of preventing a primary (first) cancer, there is also evidence proposing that weight-loss, when combined with a healthy lifestyle, may be associated with a decreased risk of recurrence of the primary cancer [40] and the appearance of metastatic, as well as a significant decrease in non-cancer related morbidity and mortality among cancer survivors [41]. Furthermore, a systematic review and meta-analysis established that metabolic surgery was associated with an impact in decreasing incidence of cancer in the populations studied and the overall cancer incidence and occurrence of obesity-related cancers were both reduced in patients who had undergone bariatric surgery. However, when analyzing for specific types of solid cancer, bariatric surgery was only significantly associated with a protective effect in breast cancer [33].
One study compared cancer incidence of obese patients who had undergone bariatric surgery with that of the general population and found that for obesity-related cancer. The overall incidence rate ratio was 1.04 for all subjects who underwent bariatric surgery compared to the general population, implying that
bariatric surgery may decrease the risk of cancer in formerly obese subjects to a risk comparable to that of the general population [41].
The various types of surgery seem to have different effects on weight loss and cancer risk reduction: in a population-based cohort study in England [42], there was a 5-fold reduction in the incidence of hormone-related cancers (endometrial, breast, prostate) following bariatric surgery, particularly in patients who had undergone gastric bypass or sleeve gastrectomy. However, there was only a 3-fold after gastric banding.
Impact of bariatric surgery on mortality vs survival
Some studies contributed to an increasing pool of evidence suggesting that bariatric surgery is associated with better long-term survival than the usual care given to these patients like modification of lifestyle and pharmacological treatment [8, 10, 34, 41, 43].
Arterburn et al. [43] conducted a study in which, at the end of a 14-year study period where they compared two separated groups, one surgical and one match control group, there were a total of 263 deaths in the first and 1277 deaths in the matched control group. A Kaplan-Meier analysis estimated that the mortality rates were 2.4% at 1 year, 6.4% at 5 years, and 13.8% at 10 years for surgical patients, and 1.7%, 10.4% and 23.9%, respectively, in the control group, demonstrating that bariatric surgery was associated with a statistically significant reduction in all-cause mortality. There was also a significant interaction between period of surgery and mortality in the first year of follow-up, suggesting that earlier bariatric
cases had a greater risk of operative and early postoperative mortality than more recent bariatric cases.
They also found out that mortality rates were lower in diabetic patients compared to non-diabetic ones and that surgery was associated with lower long-term mortality for both super obese (BMI ≥50) patients and less obese (BMI <50) patients, even though these two last results were not statistically significant [43]. Adams et al. [8] demonstrated a 46% reduction in mortality cancer-related after a follow-up of 12.5 years for gastric bypass subjects compared to the no-surgery group of obese controls. The same group previously found a 60% reduction in cancer mortality when comparing post-gastric bypass patients to severely obese controls [38], the only difference being the additional 5 years of follow-up. The smaller risk reduction in the latter studied could be related to some degree of weight regain after surgery.
An older study made by Christou and his team demonstrated that patients being treated with bariatric surgery had a 5-year mortality reduce by 89% [34].
Another important finding was the association between the BMI or age and reduction in the risk of death. Sjöström et al. in the Swedish Obesity Study (SOS) [10] observed that the reduction in the risk of death in the surgery group was about 30% in subjects with higher BMI (above 40,8 kg/m2) and about 20% in subjects with a lower BMI (below 40,8 kg/m2). Also, the risk reduction achieved by surgery appeared much larger in older subjects (25%) than in younger subjects (6%).
Metabolic and inflammatory alterations
The primary function of white adipose tissue (WAT) is lipids storage in order to maintain energy accessibility in case of caloric deficit. In addition to its known storage function, adipose tissue is also considered an important endocrine organ because of its secretory products called adipokines. Diet induced adipose tissue expansion, as it happens in obese patients, results in alterations in adipokine secretion resulting in systemic effects, which include metabolic dysfunction, and a chronic state of low-grade inflammation, both of which are known to contribute to carcinogenesis, tumor progression and tumor spread [3].
The expansion of adipose tissue results in an invasion of macrophages which stimulate the release of pro-inflammatory cytokines like TNF-α, IL-6 [20, 44] and IL-1β, enhancing local inflammation. Also, alterations in intestinal permeability may also result in translocation of bacterial products which can contribute to the spread of the chronic inflammatory state [3]. Increased inflammatory activity contribute to further intensify the metabolic dysfunction and the insulin resistance [3]. Together, inflammatory mediators and metabolic dysfunction result in not only increased levels of insulin but also estrogen, which have stimulatory effects on human cancers. Increases in insulin will naturally increase levels of insulin-like growth factor-1 (IGF-1) which also has mitogenic properties [17].
This changes in inflammatory mediators and oxidative stress are already proven to be altered in pediatric severe obesity as well as alterations in levels of various adipokines [15].
When studying whether the blood levels of cancer-related biomarkers are altered by surgical weight loss, Farey and his group [2] found a marked decrease in the levels of human cancer-related proteins in the blood after laparoscopic sleeve gastrectomy that included the proangiogenic factors of VEGF family of growth factors, endoglin, a transmembrane accessory receptor for TGF-β, growth factors such as EGF, TGFα and heparin-binding EGF-like growth factor (HBEGF). Moreover, inflammatory mediators and adipokines like IL-6, IL-8, and TNFα were decreased; all of them with studied causal relation with cancer. This effect was achieved early, at only 12 weeks after surgery, which is presumably due to the rapidity of weight loss and improvement of metabolic disease after effective bariatric surgery. The changes induced by surgery seemed sufficiently big to insinuate that at least some of the molecular pathways are being deactivated after surgery, probably by reducing the total mass of adipose tissue and other elements such as reduced insulin and insulin receptor signaling [2]. When considered together, these results indicate that metabolic surgery improves not only the chronic inflammatory state and the increased cell proliferation but also proves that the proangiogenic cascade is reversible. The reduced inflammatory state seen in this study was supported by the results published by Askarpour et al. [44], showing a significant reduction in the levels of various inflammatory markers including CRP, IL-6, and TNF-α. Similarly, Miller et al. [14], found a decrease in the circulating levels of leptin, CRP and soluble receptor 1 for TNF-α (TNFSR1) from baseline to 6 months after Roux-en-Y Gastric Bypass (RYGB) , in addition to an increase of adiponectin during this period. The changes observed after surgery in adiponectin and TNFSR1 were apparent at 3 weeks
and no further changes were seen with more weight loss. These results supported the theory that the impulse for the changes in adiponectin and TNFSR1 might be an acute negative energy balance rather than modifications in body fat. In this latter study, no changes were seen in TNF-α, explained by its shorter life, while TNFSR1 is more stable in the circulation as has longer half-life.
Although most studies focusing on surgery effects primarily investigated changes in serum parameters, Jurets et. al. [12] investigated changes in the expression of local adipose tissue inflammation and cachexia-related genes. In agreement with a few other past studies, this group theorized that the amount of weight loss after bariatric surgery look like some cases of cachexia. Cachexia and obesity are on opposite sides of the weight spectrum, but they seem to display some similarities, both being characterized by enlarged lipolysis of adipose tissue and insulin resistance [12]. When analyzing changes in subcutaneous adipose tissue (SAT) gene expression after metabolic surgery, this group reported that the gene expression profile of adipose tissue inflammation-associated genes of the surgery group was significantly different when compared to the obese and even lean control group and pointed to reduced inflammation. This study was meant also to show that weight loss affected not only genes relevant to lipolysis and apoptosis, but also growth factors. There was a large upregulation of tumor necrosis factor (TNF) expression, a known cachexia-inducing factor, in the post-obese group (up to 2.9-fold higher after weight loss). These was also a downregulation of metabolic markers such as adiponectin, insulin receptor substrate 2 (IRS2), peroxisome proliferator nuclear receptor gamma (PPARG),
and glucose transporter type 4 (GLUT-4) expression. These alterations after weight loss indicate a reduced metabolism in adipose tissue. Although insulin pathway genes were downregulated, whole-body insulin sensitivity was restored in the surgery group. The expression of TNF in SAT following metabolic surgery looked to be an independent factor for whole-body insulin resistance, diverging to the obese state. Local insulin resistance seemed to happen in SAT in a similar way that happens in cachectic states, reflecting difference of effects of metabolic surgery on adipose tissue and on systemic factors [12].
Endometrial cancer
Increasing adiposity in women is associated with an increased conversion of adrenal androgens to estrogenic precursors, decreased sex hormone binding globulin, increased insulin-like growth factor and decreased progesterone production as a result of impaired ovulatory function. This leads to estrogen– progesterone imbalance, which has been associated with the development of endometrial hyperplasia and adenocarcinoma, similarly to estrogen-only hormone replacement therapies [45].
Prospective studies have shown that the endometrial cancer (EC) risk increases 1,6-fold with each additional 5kg/m2 in BMI (by an IMC of 42 kg/m2, the risk is 9,1-fold higher) [26, 27].
In light of the epidemic rates of obesity, the incidence of endometrial cancer is rising [16, 26] and it’s crucial to understand if there is effective way to prevent it.
Three pathways are thought to be involved in the development of EC cancer and might explain why obese women are at risk: an inflammatory pathway demonstrated by chronic inflammatory state, a metabolic pathway with insulin resistance and a hormonal pathway with steroid hormone imbalance [26]. C-reactive protein (CRP), interleukine-1 receptor α (ILR-1 α) and IL-6 are some of the inflammatory biomarkers that have been linked with increased risk of EC cancer and that were prove to be also increased in obese women [27] .
Bariatric surgery-induced weight loss appears to significantly reduce this risk of endometrial pathology [16, 25, 26, 30, 39, 40]. Ward et. al. [40] demonstrated that bariatric surgery is associated with a 71% reduction in risk for uterine malignancy, with similar results in other studies, for example the SOS. In this latter study, a 24% reduction in incident cancers was seen among women who underwent bariatric surgery, in comparison with controls, over a 12.5-year follow-up period but the most notable reduction in cancer risk was for EC, that showed a seven-times risk reduction [10]. These effects are also sustained by the stabilization of EC risk biomarkers with weight loss after bariatric surgery verified in other studies [26].
One of the most dramatic effects of bariatric surgery is a decrease in insulin resistance as early as 6 days after surgery. As insulin resistance improves, the levels of sex hormone binding globulin (SHBG) increase. Along with a decreased peripheral conversion of aromatase to estradiol, this leads to a decrease in bioavailable estrogen [40]. Aline with these results, Anveden [25] reported a greater risk reduction of female-specific cancer in women with medium or high insulin levels at baseline compared to those with low insulin levels [25]. This is a
likely the explanation for Argenta's [16] finding in a study of endometrial biopsies obese women. Of the 4 women with hyperplasia, 2 resolved without additional treatment after weight loss surgery (WLS). These outcomes were supported by MacKintosh [30], that found a sustained resolution of atypical hyperplasia after bariatric surgery in obese women, with reductions in endometrial Ki-67 (marker of cell proliferation) and hormone receptors and also a reestablishment of glandular PTEN (tumor suppressor) expression with weight loss. These biomarkers were all altered before surgery and reflected a pro-proliferative environment.
Morbidly obese women that have no symptoms of malignancy certainly represent a subpopulation that stand at a higher risk and could benefit with the implementation of screening exams, since the prevalence of endometrial pathology is around 10% in these subjects [16]. As bariatric surgery plays a beneficial role in pre-malignant conditions such as endometrial hyperplasia [39], this cloud be an option to treat this women in the future.
African American (AA) women could particularly benefit from bariatric surgery not only because obesity is more prevalent among them when comparing to European American (EA) women but also because it has been reported that AA women have higher grade and stage tumors, a more aggressive histology and recurrence, with lower survival rates (2-fold higher mortality rate) [27].
Breast cancer
Obesity is associated with increased activity of the aromatase enzyme and with higher levels of hormones such as estrogen [40, 45] as well as pro-inflammatory cytokines [44] which can cause macrophage migration to breast tissue leading to epithelial proliferation, all of which increase the risk of breast cancer. Also, obese women with breast cancer diagnosis have a higher risk of mortality when compared with normal-weight women [46], possibly due to comorbidities associated. The increased incidence of breast cancer was seen in all types of cancer but was higher mainly at the expense of estrogen receptor (ER)-positive breast cancer [47].
Weight loss has been studied for years as a way to prevent the increase cell proliferation seen in these patients, particularly intentional weight loss through metabolic surgery. Several studies have confirmed a reduction in obesity-related solid cancer incidence following bariatric surgery with the greatest protection being provided to women, especially due to a marked reduction in breast cancer risk [31, 33].
Both bariatric surgery (considering all procedures together) and RYGB (alone) were independently associated with reduced HER2+ tumors [48].
Surgery not only can reverse obesity but also positively impacts systemic and adipose inflammation, the metabolism and diet composition, all pathways that have been shown to impact breast cancer biology in obesity [49].
Additionally, metabolic syndrome and insulin resistance, both conditions of obese patients, are associated with mammographic dense breasts, particularly in
premenopausal women [49]. Several studies have demonstrated the increased risk of breast cancer with the increase of breast density on mammography [24, 49, 50] and in most patients, surgery caused a significant reduction in the all-body adipose tissue and in the breast cancer risk. This all-body fat reduction is expected to increase breast density due to the inverse correlation of mammographic density with BMI, but actually, a decrease in breast cancer risk happens after WLS [50]. Density includes two components, the fibroglandular tissue and adipose tissue. WLS is likely to change both these components. With the improvements in the metabolic status after WLS, both physical and biologic changes in the fibroglandular part of the breast can also significantly contribute to the decrease in breast cancer risk [50]. Vohra et. al. [24] sought to determine the effect of WLS on volumetric breast density (VBD) and fibroglandular volume (FGV) in African American and white obese women. It was stated that obese women that underwent WLS had a significant increase in percentage of VBD after surgery, a fact that was not unexpected, since adiposity and density are inversely correlated with one another. Also, a significant decrease in FGV following WLS in the study population as well as in the subset of postmenopausal women, was observed. Both FGV and percentage of FGV have been described to be more accurate predictors of breast cancer risk than percent dense area [24].
Moreover, recent studies have documented an increased risk of complications following breast cancer treatment with both unilateral mastectomy and subsequent breast reconstruction with increasing BMI. At a matched BMI, both bariatric surgery and control cohorts had equivalent surgical outcomes, including the use of breast conserving therapy, plastic surgical reconstruction, need for
tumor re-excision, and surgical complications. However, the bariatric surgery group lost, on average, 11 kg/m2, before their cancer and reconstructive surgery [48].
Another study supporting this idea, found that survival among obese women with breast cancer was worse than survival among non-obese women, with a 33% of increase in the rate of death among obese women. The obesity effect was larger in pre-menopausal (HR=1.47) than post-menopausal (HR=1.22) women but the difference was not statistically significant [46]. This meta-analysis of 43 studies showed that bariatric surgery also influences also the rate and aggressiveness of tumor development. Earlier cancer stage in a few cases of tumors seen in the bariatric surgery cohort was mostly due to earlier detection of the tumors [46]. In a systematic review by Winder et.al. [51], the total number of breast cancers diagnosed in the bariatric surgical group was 114 (1.2%) and that in the control group was 516 (3.1%) and the overall analysis showed that bariatric surgery was associated with a statistically significant reduction in breast cancer diagnosis at follow-up.
Pancreatic cancer
Pancreatic cancer is one of the most aggressive malignancies, with no effective screening method available currently, usually diagnosed in an advanced and incurable stage. Thus, the identification of modifiable risk factors is important so that preventing measures are set in practice.
Several studies have now established a causal relation between obesity and pancreatic cancer [21, 22, 52]. A meta-analysis of prospective studies [21] supported a positive association between BMI and risk of pancreatic cancer in both men and women. Overall, a 5 kg/m2 increase in BMI was associated with a 12% increased risk of pancreatic cancer. All studies included showed an approximately 2-fold elevated risk of pancreatic cancer with obesity.
One other cohort study found that men and women who reported ‘‘central’’ weight gain had a statistically significant increased risk of pancreatic cancer compared with those who reported ‘‘peripheral’’ weight gain. Sample evidence from in vitro, animal and human studies included in this meta-analysis indicated that abnormal glucose metabolism and insulin resistance may be implicated in the development of pancreatic cancer, supported by Huxley et.al. that found a higher risk of pancreatic cancer associated with long-standing diabetes [53].
Berrington de Gonzalez et.al. [22] reported similar results from their study, with 19% higher risk of pancreatic cancer for obese people.
He et.al. [52] performed an experimental study in mice to prove that RYGB prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in Ngn3-Tsc1−/− mice. This hypothesis was based on the fact that rapamycin (mTOR), a major known regulator of cell growth, controls most of anabolic and catabolic processes in response to nutrients and nutrient induced-signals, as over-nutrition increase mTORC1 signaling [54]. RYGB surgery was found to inhibit the occurrence and growth of pancreatic ACC by suppressing the mTORC1 signaling.
Liver cancer
Metabolic surgery can have an important role in liver cancer prevention [23] as associated changes may improve several alterations of the spectrum of non-alcoholic fatty liver disease (NAFLD), including steatosis, steatohepatitis, and fibrosis, and eventually lead to complete resolution of NAFLD or nonalcoholic steatohepatitis (NASH), its most severe form [55]. As the prevalence of NAFLD is estimated to be about 70% in obese individuals, 95% in patients with morbid obesity and 18,5% and 33% for NASH, respectively [56], these individuals have a much higher risk to progress to more serious conditions like hepatocellular carcinoma [57]. So, it’s reasonable to believe that bariatric surgery could benefit morbidly obese individuals in the prevention of liver cancer as it resulted in an improvement of histopathologic features of NAFLD [23, 56, 57] in more than three fourths of the patients [55].
The association established between metabolic surgery and the reduction of liver cancer risk was largely studied and it appears to be altered by race, as the PR value being considerably lower among black populations when compared to white-ones, but this effect can be due to the confounding factor of socioeconomic status, as those who could afford the surgery may have better access to health care, and subsequently, lower likelihood of developing cancer [23].
Negative and significant correlations between the levels of adiponectin and the severity of both liver fibrosis and steatohepatitis have been found, signaling a protective effect of adiponectin in regard to the progression of NAFLD to more aggressive forms, such as cancer. This function may be potentially linked to the
anti-inflammatory properties of adiponectin, as well as its insulin sensitizing effect, both effects being likely to act together to damage the liver [58].
A meta-analysis conducted by Mummadi et. al. [55] reported that the majority of patients submitted to surgery experienced complete resolution of NAFLD and the risk of progression of inflammatory changes and fibrosis seemed to be minimal. The most striking improvement noted was in steatosis, followed by steatohepatitis and fibrosis.
Horvath and his team [6] tried to analyze the relationship between high BMI and the DNA methylation ages of human blood, liver, muscle, and adipose tissue and concluded that on average, epigenetic age increased by 3.3 years for each 10 BMI units. The epigenetic age acceleration related to processes such as oxidative stress and energy metabolism, may have responsibility in liver-related comorbidities of obesity, such as liver cancer and this effect seems to be independent of the presence of NASH. Future liver cancer screening guidelines may be influenced by these results [6].
Colorectal cancer
The effect of bariatric surgery on colorectal cancer (CRC) or premalignant lesions risk is not fully understood. The data available in the published studies show contradictory findings mainly due to overall short follow-up periods and poor standardization between bariatric patients and appropriate controls risk adjusted for main CRC risk factors may contribute to these conflicting results. Also, it has been hypothesized that the increased risk of CRC after surgery seen in some
studies results may be due to the excess body weight that some individuals still have despite WLS [59].
A propensity case-control study [60] with a mean follow-up of 7,8 years concluded that surgery was associated with reduced risk-adjusted incidence of the diagnosis of new colorectal lesions by 38% compared with propensity matched controls who did not undergo bariatric surgery and found no difference in the number of new polyps formed, types of polyps found, or overall CRC TNM staging between the patients in each group who developed new colorectal lesions but they did find that none of the control patients had evidence of metastases at the time of the new CRC diagnosis, while metastases were present in 3 of the 5 (60%) new CRC patients in the surgery group. Despite this, the number of new cases of CRC is too low in both cohorts, which makes it difficult to take any conclusion about the clinical implication of these results.
This result was in concordance with another meta-analysis, revealing that bariatric surgery was associated with a 27 % lower subsequent risk of CRC diagnosis [19].
An older experimental study [20] compared mucosal biomarkers of epithelial cell proliferation, apoptosis, and crypt branching in the rectum of morbidly obese and normal weight individuals and then studied the effect of weight loss in the same individuals that underwent RYGB so that it was possible to test whether weight loss in obese individuals lead to a change in rectal mucosal biomarkers. It was found that obese patients had increased proliferation of rectal epithelial cells (showed by a mean number of mitoses per crypt and crypt area significantly higher), compared with lean individuals, which is not balanced by an increased
level of epithelial cell apoptosis, thus leading to increased crypt size. When analyzing the effect of WLS on elevated mucosal biomarkers there was a surprising and highly significant 2-fold increase in the number of mitoses per crypt in rectal mucosa, associated with a change in the distribution of the mitotic epithelial cells in crypts [20]. Despite this, there was no significant increase in mean crypt area and no increase in the number of branching crypts but there was an overall decrease in the number of apoptotic cells per crypt. They also measured serum levels of TNFa and macrophage migration inhibitory factor (MIF) as they have been linked with colorectal mucosal inflammation and carcinogenesis; the value was higher before RYGB when compared with individuals with a normal BMI and both increased significantly even further following RYGB.
Furthermore, consistent with the reduction in serum IL-6 levels post-RYGB, there was a significant decrease in IL-6 protein immunoreactivity in mucosa collected 6 months (appropriate time to exclude a nonspecific mucosal response to abdominal surgery) after RYGB compared with paired preoperative mucosa but there was also an overall significant increase in IL-6 mRNA levels. However, it was not well-defined if the hyperproliferative state observed 6 months after was in fact a brief phenomenon or if it was going to persist for longer periods. The duration of this response is clinical important because persistent elevation of this biomarker of colorectal cancer risk would imply that obese patients, who have undergone RYGB, are at long-term increased risk of colorectal neoplasia [20]. Later, Derogar et. al. [59] conducted a retrospective cohort study from January 1, 1980 to December 31, 2009 so the follow-up time was longer and found that
obesity surgery was associated with an increased risk of colorectal cancer with time after surgery, whereas no such pattern was found in the obese patients who did not undergo obesity surgery. The same group reported that patients who underwent GB exhibited rectal mucosal hyperproliferation that persisted for at least 3 years after surgery, associated with increased mucosal expression of the protumorigenic cytokine MIF.
These observations were recently analyzed by Tao et. al. [18], that reported that previous obesity surgery had a negative prognostic impact on cancer survival, with 3-fold higher rates of cancer deaths in patients with rectal cancer (but not colon cancer) when compared to obese controls.
Mackenzie et. al. [42] also reported a greater than 2-fold increased risk of colorectal cancer following GB and Aravani et. al. [31] demonstrated that elevated CRC risk continues after surgery, in individuals who underwent it over the age of 50 years.
One other meta-analysis performed failed to reproduce the increased risk of colorectal cancer with surgery, although it may be suggested that there was a trend towards a slight increased risk of colorectal cancer development [33]. However, Afshar et. at. [11] showed a decrease of 34% in the mean number of mitoses per crypt and a reduction of the crypt proliferative compartment at 6.5 months after RYGB, accompanied by a decrease in expression of the pro-inflammatory gene COX-1 in the rectal mucosa. Despite this, the changes on the pro-tumourogenic and pro-inflammatory genes were not significant (MIF, c-FOS and c-JUN; and COX-2 and IL-6, respectively) [11].
Esophageal adenocarcinoma
Obesity is a recognized and studied risk factor for the development of esophageal adenocarcinoma (EG). Chronic gastroesophageal reflux disease (GERD) and subsequent development of Barrett’s esophagus are the leading cause for the increased incidence of cancer in such individuals. Pathophysiologic mechanisms leading to GERD in obese patients involve the presence of hiatal hernia, weak lower esophageal sphincter (LES), transient LES relaxation, altered gastroesophageal pressure gradient, and esophageal factors (for example, poor esophageal clearance and altered esophageal motility) [61]. Although these are the most important factors, other reflux-independent mechanisms can be involved, such as low-grade chronic inflammatory state, metabolic syndrome with increased circulating hormones with carcinogenic effect, including insulin and insulin-like growth factor [62].
However, in these days, with the obesity epidemic, an increasing number of bariatric surgeries are being performed worldwide and some cases of esophageal cancer after metabolic surgery are being reported. Esophageal cancer after surgery was considered rare and the majority, in the past, were only published as sporadic case reports [62].
More studies are beginning to address this issue with theories concerning the possibility of a causal relationship. Reported cases of gastric carcinoma classically arise in a milieu of intestinal metaplasia, atrophy, and foveolar hyperplasia both in restrictive procedures and in Roux-en-Y Gastric Bypass (RYGB) remnant [62]
First, anatomical modifications after surgery may increase carcinogenesis [63] and after putting together case reports, it seems that for esophagogastric neoplasms after restrictive bariatric procedures, (i.e., gastric banding, vertical gastric banding (VGB) and sleeve gastrectomy (SG)), the main pathophysiologic explanations are chronic GERD, which can promote Barrett’s esophagus development; some degree of gastroparesis with stasis of food and gastric acid in the pouch causing chronic mucosal irritation; and local irritation caused by the presence of the gastric band, supported mainly by the alterations frequently found in the transitional mucosal zone [62]. Chronic GERD may represent an important risk factor, because the association between restrictive procedures and de novo or worsened GERD symptoms has been clearly described [61]. However, recent study showed lower aggressiveness in a subset of EG cancer detected after bariatric surgery [64].
Bariatric patients usually follow a strict follow-up after the procedure; therefore, some cases can be diagnosed at an early stage [64], representing an overestimation of cases, so it’s important to recognized that an accurate conclusion about the eventual relationship of some bariatric procedures with EG cancer cannot be reached.
Although the incidence of esophagogastric cancer in patients with a previous bariatric procedure, namely in patients with an excluded stomach, does not seem to be that much greater than in the general population, it is critical to take in count that patients who have had bariatric surgery represent an ever-increasing population that includes many adolescents [62].
DISCUSSION
Bariatric surgery offers a substantial weight loss and for that it is considered to be the most efficient and sustainable way for losing weight, if the whole therapeutic regime if correctly followed. It offers an average loss of 27% of the initial weight [32] and depending on the type of surgical procedure used, the amount of weight loss can even higher: GB and sleeve gastrectomy have been shown to result in more weight loss compared with gastric banding [42].
With this weight reduction comes also a decrease in cancer risk [3, 8, 32, 33, 41, 42]. Schauer et. al. [32] found a 14% cancer risk reduction per each 10% of the initial weight loss. Oddly, this association was only statically significant for non-obesity-related cancers [32], showing that there is an overall cancer risk reduction with surgery. Despite the importance of the amount of weight loss proved by the higher influence on hormone-related cancer risk reduction with GB and SG [42], the non-statically significant result may indicate that there could be other important modifications after metabolic surgery that reduce this risk.
Although we can focus the use of bariatric surgery to its cancer risk reduction, it shouldn’t be forgotten that early diagnosis of malignant pathology in obese patients is difficult because they often don’t present with evident signs and it’s common that the cancer only turns apparent when in an advanced phase, where the treatment is a lot more complicated and the mortality is higher. So, substantial weight loss should also make the detection easier. Also, surgery patients tend to have a stricter follow-up which facilitates the process of diagnosis.
Metabolic surgery is associated with better long-term prognosis than standard and initial care with lifestyle modifications and pharmacological treatment and also reduces all-cause mortality [8, 10, 34, 41, 43] and recent studies suggest that current cases of WLS have even lesser rates of mortality and morbidity [43], as the surgical techniques improve and surgeons become more experient in this kind of procedure.
The interesting discover by Arternurn et. al. [43] that the mortality is lower in diabetic patients that went metabolic surgery that in non-diabetic patients may indicate that surgery offers a better survival change in patients with more co-morbidities. However, this result was not statistically significant, but it can be explained by the small sample size and also by the short-term follow-up. These results are in agreement with the ones on SOS, that stated that risk of death reduction was higher in older and heavier patients, that, again, tend to have more comorbidities and complications when compared to young obese patients. So, these individuals are the ideal target to benefit from metabolic surgery.
Metabolic surgery represents not only a way to improve survival in obese individuals, reducing the 5 year mortality rates by 87% [34], restoring health and quality of life, improving the obesity-associated medical conditions, that either resolve or improve with surgery [3], but it also lowers the risk of obesity-related cancers at least to some degree.
It is well established that metabolic and hormonal dysfunction, for instance, insulin resistance, a hyperglycemic state and increased estrogen levels, as well as chronic inflammatory state and its oxidative stress contribute to the creation of an oncogenic environment that leads to cytologic alterations and tumor formation
[3]. The alteration of adipokine secretion and the release of pro-inflammatory cytokines in the WAT in expansion like TNFa and IL-6; growth factors such as EGF and TGFa; and proangiogenic factors such as VEGF and VEGF-family are the basis to the generalized chronic and low-grade inflammatory state [2]
As insulin levels increase due to insulin resistance, the levels of IGF-I also increases and this mediator have known mitogenic properties that increase tumor risk [17].
These alterations were proved to be already found in pediatric cases of obesity and reflected the importance of obesity prevention and treatment as adolescents to prevent the long-term adverse outcomes in adult life [15].
Given these aspects, metabolic surgery gained its “metabolic” denomination because it goes beyond weight loss. It’s associated with improvement of all the previous discussed metabolic alterations [2].
Although most studies focused in the serum amelioration of pro-inflammatory and metabolic markers, one study by Jurets et.al. [12] focused on changes in local expression of adipose tissue inflammation and cachexia-related genes based on the premise that weight loss resembles cachexia. They found that surgery caused a specific pattern in SAT gene expression; TNF local expression was upregulated (a cachexia-inducing factor) in the surgery group but not in the control group, accompanied by a downregulation of adiponectin (anti-inflammatory adipokine), IRS2, PPARG and GLUT4, pointing to a decrease in adipose tissue metabolism. There was also found a local insulin resistance in SAT, contrary to its serum levels. These alterations made possible the assumption that rather than a lean and healthy state, metabolic surgery may give rise to a cachexia-like state, the
opposite end of weight spectrum. For a more in-depth analysis of the biological processes occurring in different human fat depots during weight loss, the mechanisms through which these changes contribute to whole-body metabolism need to be investigated in further studies [12].
Obese women are particularly high risk because increasing adiposity is associated with estrogen-progesterone imbalance [45] that is in the origin of the development of premalignant and malignant lesions like endometrial hyperplasia and adenocarcinoma, respectively.
Bariatric surgery appears to significantly reduce the risk of endometrial pre- and malignant pathology [16]. The mechanisms behind seems to be linked with improvement of EC risk biomarkers and include a return to the normal balanced values of estrogen, sex hormone binding globulin (SHBG), IGF and progesterone [45] and inflammatory markers such as CRP, IL-6, ILR1-a. Also, there is a decrease in insulin resistance (that per se lowers the estrogen levels and increases SHBG) and improves proliferation markers such as Ki-67 and PTEN [30]. The EC risk reduction can reach the 9-fold [26, 27].
As malignant or pre-malignant lesions are more common in obese women and the improvements that bariatric surgery proved to have, an active screening should be performed as well as earlier introduction of definitive therapy that can begin with metabolic surgery, may be a solution to reduce mortality and morbidity in these subjects [16], [51]. This is an important aspect, particularly in AA obese women that have, not only higher incidences of malignant endometrial pathology but also higher grades and staging tumors, with more recurrence rates and lower survival rates [27].
One other type of malignancy that seems to be related with the same mechanisms as endometrial cancer in obese women is breast cancer [40], [44], [45]. The most frequent type of breast cancer found in these population is the ER positive, which is in agreement with the mechanisms responsible for the increased risk of cancer in obese women. Obesity seems to be linked with a 33% increase in death rate, when comparing obese women with non-obese women, both with breast cancer [46].
It was hypothesized that surgery was associated with a marked reduction in breast cancer risk and the results showed that, of all obesity-related cancer, breast cancer was the one that had a greater risk reduction [31], [33]. Additionally, it also influences positively the aggressiveness of tumor development [46] and its prognosis, particularly the surgical outcomes such as the use of breast conserving therapy, plastic surgical reconstruction, need for tumor re-excision, and surgical complications [48].
Metabolic surgery also changes breast density [50] mostly by influences on the fibroglandular component, which contributes significantly to the cancer risk reduction [24].
This data showed a beneficial effect of bariatric surgery and may be helpful to surgeons in prioritization of patients for bariatric procedure. Women with a strong family history or higher baseline risk of breast cancer may have a greater risk reduction [51].
Pancreatic cancer is one of the most feared malignancies due to its late diagnosis, usually in an advanced and incurable stage, with little or no effective treatment options to offer. Because its well establish that obesity is associated
with increased risk of pancreatic cancer [21, 22, 52] and that this risk can reach 19% [22], it is important to consider preventing options, such as obesity surgery. Central weight seems to be associated with an even higher risk of pancreatic malignancy, when comparing with peripheral weight gain, thus highlighting the importance of SAT in cancer development [53]. One other important risk factor found was a history of long-standing diabetes mellitus.
RYGB has now been studied in mice as a possible way of reducing the pancreatic cancer incidence in obese patients, especially when talking about patients with co-morbidities such as diabetes. The results showed that surgery prevent the occurrence and growth of pancreatic ACC, but further investigation is needed to prove the same relation in humans [52].
Obesity is correlated with liver alterations, particularly the ones belonging to the NAFLD spectrum; the most severe form is NASH and it leads to progression to fibrosis or hepatocellular carcinoma [55].
As obesity surgery is thought to resolve [55] or improve the histopathologic features of NAFLS, it can be used as way to prevent premalignant and malignant liver injury [23, 56, 57]. Adiponectin, lower in obese patients, have been studied as a NAFLD protector and inhibits the progression to more serious complications [58]. Since bariatric surgery leads to increases in the levels of adiponectin [14], it is reasonable to assume that this mechanism is involved to some degree in the significant improvement of NAFLD described after surgery and therefore a risk reduction of liver cancer.
The acceleration in epigenetic ages that occurs with obesity and obesity-related oxidative stress, inflammation, altered metabolism, were found to increase the
risk of liver cancer, independently of the presence of NASH previously. When put all together, these results make the risk of liver cancer even higher.
The most confounding results about the impact of metabolic surgery on cancer incidence lie on gastrointestinal cancers, including esophageal and colorectal cancers.
The fact that metabolic surgery acts as a way of decreasing the chronic-low grade inflammatory state, a way to restore insulin sensitivity, to improve oxidative stress, alter hormonal secretion, suggests that the overall risk of cancer lowers after metabolic surgery and this was the thought for all types of obesity-related cancers. However, this is a still open discussion because some studies clearly showed that there was an increase in colorectal cancer incidence after surgery [20, 31, 42, 59] and various hypothesis were made to explain these results. However, also recent study showed a decrease in cancer incidence with surgery [11] and also theorized that the increase in cancer risk may be due to the still high BMI value after surgery of the included patients, compared to lean individuals or may be due to a long-term exposure to obesity-related alterations [59].
Is it yet not fully established whether colonoscopy follow-up is necessary after gastric bypass and this issue requires more research to establish the possible association and to weigh benefits against the costs beneath such exams. Nevertheless, the available research taken together indicate a fundamental role for prompt colonoscopy in patients who present with bowel symptoms following gastric bypass surgery [42].
Changes in rectal mucosal crypts and increased levels of TNFa and MIF lead to believe that maybe there’s an increase in the intestinal mucosal inflammatory
state that persists. Despite the decrease in immunoreactivity in rectal mucosal IL-6, there was also an increase in IL-6 mRNA levels 6 months after surgery. If the increase expression translates into increase expression overtime, there might be a long-term risk [11].
Bariatric surgery seems to aggravate the scenario of the obese individuals with a rectal cancer diagnosis, but this relation was not established for colon cancer. This could suggest a more specific subgroup of patients that could benefit more from surgery. Nevertheless, these findings from all-cause mortality, and therefore survival were mainly influenced by disease-specific mortality.
On the opposite hand to these findings, a 2-year-old study stated that a decrease in 34% in mitoses per crypt and decrease in crypt proliferation was linked to obesity surgery. There was also found a decrease in pro-tumourogenic biomarkers and pro-inflammatory gene expression [11]. When compared to Sainsbury et.al. [20] study, one of the first on this subject, the mean BMI was higher in the latter’s surgery group (12 kg/m2 higher) and RYGB procedures were performed with longer limb lengths, associated with hyperproliferation through malabsorption and exposure to harmful luminal content, all of which could contribute to the differences of results.
The mechanisms that lead to an increase of CCR risk related to RYBG seems to be various and possibly acting together to create a protumorigenic environment and they include the shift in bile acids homeostasis, the change in gut microbiota, the anatomical rearrangement of the gut and the significant changes in the secretion of satiety- related intestinal peptides such as glucagon-like peptide-1
(GLP-1) [65]. None of these have been clearly correlated with increase colorectal cancer risk so more studies need to address this type issue.
It also seems possible that the various types of surgery could impact differently the outcome. Malabsorptive procedures such as RYBG and BPD are more likely to cause mucosal proliferation and inflammatory changes due to a long-term exposure and contact with not absorbed luminal content, especially when comparing to restrictive surgeries.
When talking about esophageal cancer, not a lot of studies have focused its attention to this issue because the number of cases is relatively small but starting to grow. Since bariatric surgery contributes to reduce GERD and chronic inflammation [62] it was logical to thought that bariatric surgery would decrease the cases of EG. But instead, with the increasing numbers of surgeries performed worldwide is also increasing the number of EG cancers, being especially true to restrictive procedures and the cause appears to be caused by a permanence or worsen of GERD with choric exposure to acid content and Barret’s esophagus development [63]. Moreover, gastroparesis with mucosal inflammation and serosal irritation caused by the presence of gastric band could also act to increase the risk [62].
However, EG aggressiveness decreases after surgery [64]. This could be explained by the amplification of the risk when considering obesity and GERD together, both independently associated with EG cancer. When the obesity factor is controlled, it is possible that it changes prognosis.
It is actually difficult to assess if certain cases of cancers, as they have occurred a few months postoperatively, in most cases without preoperative endoscopy, are
really caused by bariatric surgery or if they were most likely present at the time of bariatric surgery and were missed [64].
CONCLUSION
Metabolic surgery is associated with an overall cancer risk reduction and cancer prevention. Its effects can be directly linked with the amount of weight loss after surgery but also indirectly linked with the anatomical changes and its systemic metabolic modifications and decrease of comorbidities, all implicated with cancer risk. In fact, the metabolic alterations seem to have a much important role in risk reduction than initially thought.
The positive effect of metabolic surgery on hormone-dependent cancer risk, such as endometrial and breast cancer is unanimous in the studies included, as well as pancreatic and liver cancer.
As for gastrointestinal cancers, for example esophageal adenocarcinoma and colorectal cancer, the studies tend to disagree on whether metabolic surgery has a protective effect or if it further increases the risk. For colorectal cancer, recent studies pointed out that the anatomical alterations after surgery tend to change the intestinal microbiome and bile secretion, which may lead to the increase number of cases.
As obese women are at a particularly high risk of breast and uterine malignant lesions, there should be a stricter follow-up in this particular subgroup, keeping in mind that metabolic surgery could be an effective way of prevention such lesions and decreasing the mortality/morbidity associated.
CONFLICT OF INTEREST
The authors declare no conflict of interests.
AUTHOR’S CONTRIBUTIONS
Author 1
Conception of the work, design of the work, acquisition of data, analysis of data and interpretation of data. Drafting the work.
Author 2
Revising the work critically for important intellectual content. Final approval of the version to be published.
Author 3
Revising the work critically for important intellectual content. Final approval of the version to be published.
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