Using data from the KNHIS, we investigated how metabolic diseases, such as high blood pressure, diabetes, dyslipidemia, and obesity, affect the incidence of oral cavity cancer. The risk of oral cavity cancer increases in patients with a low BMI. In addition, high TC and LDL levels showed a protective effect against oral cavity cancer. In the case of diabetes mellitus, the risk of oral cavity cancer increased in both males and females, whereas HTN increased the risk of oral cavity cancer only in males.
Metabolic syndrome is a risk factor for oral cancer in males. When analyzed by sex and age, metabolic syndrome was a risk factor for oral cavity cancer only in young males aged < 50 years, and the risk of oral cavity cancer increased as the number of factors constituting metabolic syndrome increased.
Alcohol and smoking are the most common causes of cancer.(Gandini et al., 2008; Goldstein et al., 2010) Betel nut chewing, HPV infection, exposure to sunlight, mechanical stimulation due to dentures or teeth, damage by heat, chemical stimulation, Plumer-Vinson syndrome, poor oral defiance, syphilis, lichen planus, and submucous fibrosis are known to be associated with oral cavity cancer.(Goldenberg et al., 2004; Kerawala et al., 2016; Kreimer et al., 2005) Metabolic syndrome has an increasing incidence worldwide as the prevalence of diabetes and obesity increases, affecting various diseases. Recently, it has been reported that metabolic syndrome increases the risk of various cancers. However, the relationship between metabolic syndrome and oral cancer is unclear.
Several studies have investigated the association between metabolic syndrome and cancer. According to one study, middle-aged males with metabolic syndrome are more likely to develop prostate cancer. The association between metabolic syndrome and the risk of prostate cancer was stronger among overweight males than in lighter males.(Laukkanen et al., 2004) According to another study, inflammatory and angiogenic changes because of underlying insulin resistance and fatty liver disease will likely increase the incidence of hepatocellular carcinoma.(Siegel & Zhu, 2009) In one study, metabolic syndrome, obesity, and a large waist circumference were found to be associated with an increased risk of endometrial cancer.(Esposito et al., 2014) In a cohort study from the United Kingdom, metabolic syndrome, central obesity, and hyperglycemia were associated with an increased risk of pancreatic cancer.(Xia et al., 2020) In several studies, metabolic syndrome was associated with an increased risk of colorectal cancer incidence and mortality.(Esposito et al., 2013; Esposito, Chiodini, Colao, Lenzi, & Giugliano, 2012; Stocks et al., 2008) However, few studies have been conducted on the relationship between oral cavity cancer and metabolic syndrome. Unlike in other studies, there was no association between metabolic syndrome and oral cavity cancer in the current study when sex was not considered. When considered separately by sex, it was confirmed that metabolic syndrome only increases the risk of oral cavity cancer in males. In particular, metabolic syndrome increased the risk of oral cavity cancer by 1.43 times only in males aged < 50 years. In contrast to other studies on cancer and metabolic syndrome, the risk of oral cavity cancer was found to depend on the number of components of metabolic syndrome. In males with one to two metabolic syndrome components, the risk of oral cavity cancer increases 1.089 times. In contrast, when the number of metabolic syndrome components is three or more, the risk of oral cavity cancer is increased by 1.187 times. In young males with one to two metabolic syndrome components, metabolic syndrome increases the risk of oral cavity cancer by 1.187 times. When the number of metabolic syndrome components is three or more, metabolic syndrome increases the risk of oral cavity cancer 1.439 times. The risk of oral cavity cancer in young males was related to insulin resistance, high blood pressure, high blood glucose levels, and abnormal lipid levels, and an increase in the components of metabolic syndrome significantly affected the risk of oral cavity cancer.
In other cancers, obesity increases the risk of cancer occurrence. However, lean patients tend to have an increased risk of oral cavity cancer. One study explained that obesity upsets the balance of hormones and causes metabolic disorders, which increases the risk of cancer.(Calle & Kaaks, 2004) The association between oral cavity cancer and obesity remains unclear, with conflicting results between the risk of head and neck cancer (HNC) and obesity. Several studies have reported that HNC and obesity are not related.(Gaudet et al., 2012; Hashibe et al., 2013) Other studies have reported that a high BMI and central obesity lower the incidence of HNC.(Chen et al., 2019; Etemadi et al., 2014),39,40,41 In addition, there are reports that prognosis is better in obese patients because obesity plays a defensive role in malnourishment, immune disability, and cachexia induced by dysphagia or poor appetite after HNC surgery. Cigarettes, the main cause of oral cavity cancer, are known to secrete many carcinogens, causing intraoral DNA damage.(Etemadi et al., 2013) According to one study, DNA damage caused by cigarettes in lean people is worse than in normal patients.(Mizoue, Kasai, Kubo, & Tokunaga, 2006) Therefore, we can assume that thin patients have a higher risk of oral cavity cancer than normal patients. Conversely, the risk of oral cavity cancer seems to be increased in lean patients due to its unique characteristics. Due to the nature of oral cavity cancer, cancer lesions are located in the oral cavity. Therefore, unlike with other cancers, there is a high probability of developing dysphagia or loss of appetite. Therefore, it can be assumed that weight loss occurred before diagnosis, and the incidence of oral cavity cancer seems to be higher in lean patients.(Alberti, Zimmet, & Shaw, 2005)
Metabolic syndrome is characterized by central obesity, dyslipidemia, hyperglycemia, insulin resistance, and HTN, which lead to various diseases, such as cardiovascular disease and cancers. First, insulin resistance, a core abnormality of metabolic syndrome, increases the risk of cancer. Insulin resistance increases insulin secretion, which results in hyperinsulinemia. Hyperinsulinemia may activate the IGF-1 and insulin receptors or disrupt IGF-binding protein to increase IGF-1 bioavailability to the IGF-1 receptors. The IGF-1 axis might result in tumorigenesis of cancers such as breast, prostate, or endometrium.(Hsing, Gao, Chua Jr, Deng, & Stanczyk, 2003; Lukanova et al., 2004; Muti et al., 2002) In addition, the hyperglycemic state increases protein glycosylation and lipid peroxidation, resulting in toxic products. When an individual has metabolic syndrome with more than three criteria as a risk factor, there is a higher probability of insulin resistance facilitating colorectal cancer.(Laukkanen et al., 2004) Metabolic syndrome is a systemic disease that can affect the oral cavity mucosa. In vitro studies are needed to examine whether oral cavity mucosa overexpressing IFG-1 receptors and IGF-1 can induce malignant lesions and cancer. Metabolic syndrome affects insulin resistance and chronic inflammation. In these states, IL-6 is involved in the regulation of immune and inflammatory responses and increases insulin resistance. The role of IL-6 in carcinogenesis is mediated by autocrine and paracrine mechanisms that stimulate angiogenesis and cell growth and inhibit apoptosis.(Pais, Silaghi, Silaghi, Rusu, & Dumitrascu, 2009; Sonnenberg & Müller, 1993) In our study, metabolic syndrome only increased the risk of oral cavity cancer in males. The HR for oral cavity cancer increased as the number of factors constituting metabolic syndrome increased only in young males aged < 50 years. A possible mechanism to explain this sex difference is the free IGF-1 and adipose tissue levels. Males have a higher circulating concentration of IGF-1, which may be associated with cancer occurrence.(Juul et al., 1994) Adiponectin, a hormone secreted by adipose tissue, has a protective effect on cancer occurrence by decreasing insulin sensitivity.(Esposito et al., 2012) Adiponectin serum levels are higher in females than in males.(Renehan, Tyson, Egger, Heller, & Zwahlen, 2008) Metabolic syndrome affects the metabolism of IGF-1, sex hormones, and sex hormone-binding globulin,(Brand, Van Der Tweel, Grobbee, Emmelot-Vonk, & Van Der Schouw, 2011; Pugeat et al., 2010; Wang, Yu, Tang, Tang, & Liang, 2019) which may cause sex differences in oral cavity cancer. The fact that metabolic syndrome increases the HR for oral cavity cancer only in young males is unexpected. To explain this result, other causes of oral cavity cancer should be considered. Alcohol consumption and smoking are the main causes of oral cancer. Older males (aged > 50 years) had a longer smoking and alcohol history than young males. Therefore, it can be assumed that longer smoking and alcohol history obscure the effect of metabolic syndrome on oral cavity cancer because of the stronger effect of smoking and alcohol consumption. In addition, the association between metabolic syndrome and oral cavity cancer in young males might be the result of genetic issues in oral cavity cancer, which is affected by metabolic syndrome. Further research is needed to evaluate how metabolic diseases affect oral cavity cancers.
The strength of our study is that it is the first cohort study of the association between metabolic syndrome and oral cavity cancer using nationwide data from Korea. Multiple variables such as age, sex, alcohol consumption, and smoking were considered to determine the effects of metabolic syndrome on oral cavity cancer.