Head And Neck Cancer And Alcohol

Introduction

Accounting for around 890,000 cases per year worldwide and causing 450,000 deaths, head and neck cancer is the seventh most common type of cancer. Occuring in the lining of the mouth, throat and voice box, head and neck cancers are further subdivided by region into the lips and oral cavity (accounting for 355,000 new cases/year), the pharynx (accounting for 302,000 new cases/year) and the larynx (voicebox), (accounting for 177,000 new cases/year). [Figures from 2018]. Most of these cancers are of the squamous cell carcinoma variety.^1,2 Cancers of the pharynx are subdivided further into the nasopharynx (behind the nose), oropharynx (middle throat) and the hypopharynx (lower throat). More rarely, cancers of the head and neck also occur in the salivary glands and the nasal cavity.

Figure 1: Anatomy of the nose, oral cavity, pharynx and larynx

Image source: Online Science Notes from Google Images

The prevalence of alcohol use disorder has increased, particularly since the COVID-19 pandemic in the UK, according to the NICE (National Institute for Health and Care Excellence). UK government statistics estimated a total of 22,644 alcohol-related deaths in the UK in 2023, a 16.5% increase from 2016. Along with tobacco smoking and infection with the human papillomavirus (HPV), alcohol use represents one of the three main risk factors for head and neck cancer. Other risk factors include marijuana use, chewing of “pan” in south east Asia, HIV/AIDS, chronic Hepatitis C and B, Epstein-Barr virus (EBV), a pro-inflammatory diet (rich in processed or red meat and fried foods), poor oral hygiene and increased body mass index (BMI). A high intake of fruit and vegetables seems to be protective, and a lower consumption of these foods is found in people with alcohol use disorder overall.³ 

Alcohol as a risk factor for head and neck cancer

Mechanisms of alcohol-induced carcinogenesis

Alcohol-induced carcinogenesis (causing cancer) is proposed to occur by several different mechanisms. Both alcohol (ethanol) and the substances into which it is metabolised (acetaldehyde and acetate) can cause damage to epithelial (surface lining cells) and to cell DNA, leading to changes that provoke cancer. The proposed mechanisms are explained below:

Solvent action on mucosa (surface lining)

Ethanol causes direct damage to the mucosal surfaces of the upper aerodigestive tract, increasing vulnerability to further insult. This is one reason why alcohol abuse and smoking together increase the chance of developing head and neck cancer more than would be expected by adding the two factors together.^3,4

Oxidative stress

Both ethanol and acetaldehyde (the substances partly responsible for “hangovers”) are termed reactive oxygen species (ROS), capable of producing oxygen free radicals that damage DNA. This can lead to mutations, inaccurate DNA repair and DNA adducts in which acetaldehyde binds to the DNA and other gene expressions, corrupting it. This DNA damage can cause mutations in the genes, which either activate cancer genes (known as oncogenes) or deactivate tumour suppressor genes.^3,5

Changing oral microbiota

Alcohol consumption (ethanol) can alter the balance of naturally occurring bacteria in the mouth and pharynx. Killing off “good bacteria” can allow other species to flourish and produce acetaldehyde from ethanol. Some of these species, whilst found normally in saliva, have the same alcohol dehydrogenase enzyme as the liver, which converts alcohol into the more DNA-toxic acetaldehyde. Neisseria species, several Streptococcus species, including Streptococcus salivarius, Streptococcus intermedius and Streptococcus mitis, as well as the fungus Candida. Lab studies suggest that antibiotics can inhibit this acetaldehyde production, supporting the link between microbial activity and cancer risk.^3,6,7

Acetaldehyde DNA adducts formation

(Repeated) Genetic polymorphisms in the alcohol dehydrogenase (ADH) genes, particularly ADH1 and ADH2, can influence how quickly ethanol is metabolised into acetaldehyde. A variant found in East Asian populations causes slower acetaldehyde breakdown, and higher accumulation is associated with a higher risk of head and neck cancer.  However, alcohol misuse disorder develops less commonly in people exhibiting these polymorphisms, as they experience an unpleasant flushing reaction when they drink alcohol due to the acetaldehyde.^8,9

Epigenetic changes

Epigenetics refers to long-term, stable changes in a cell's function without any changes occurring in the cell’s DNA sequence. In this situation, extra chemical groups are added to the DNA molecule without altering the sequence. Alcohol-induced epigenetic effects affect the cellular processes that help prevent cancer, such as tumour suppressor gene function, like programmed cell death (apoptosis) and DNA repair.³

Figure 2: Alcohol consumption and development of head and neck cancer ³

Dose-dependent risk: chronic alcohol consumption

The intensity (greater than 3 drinks daily) and duration of alcohol consumption both have an impact on head and neck cancer risk. The INHANCE database was set up in 2004 to pool the results of different studies on this subject. Interestingly, heavy-intensity drinking, even for short periods, was the major risk factor for cancers of the oral cavity, hypopharynx and larynx. In contrast, drinking intensity and duration both had equal impact on oropharyngeal cancer risk, according to a 2020 analysis of this data. ²

Interaction of alcohol with other risk factors

Synergistic effects with tobacco 

A 2009 analysis of the INHANCE data concluded that smoking tobacco and drinking alcohol increase the risk of head and neck cancer by a greater degree than the sum of their individual effects. This seems to be particularly the case in men. 80% of head and neck cancers in men were attributable to smoking and/or drinking, compared to 61% of cancers in women, although this study did not include data about the other main risk factor - HPV infection.¹⁰

Gender and genetic susceptibility

Head and neck cancers occur more commonly in people assigned male at birth compared with people assigned female at birth. Head and neck cancer is the 5th most common in men, compared to the 12th most frequent in women.¹

Polymorphisms (different forms of a gene) of the gene coding for the ADH2 enzyme that catalyses the breakdown of acetaldehyde, found more frequently in East Asia, are at greater risk of alcohol-related tumours if they drink due to buildup of acetaldehyde (although the unpleasant “flushing reaction” this causes means fewer people who carry this polymorphism drink heavily).⁹

Alcohol and HPV (human papillomavirus) interactions

The interaction between alcohol and HPV infection is difficult to quantify. This is partly because much of the available pooled data from studies such as INHANCE does not contain information about HPV status. Smaller studies have yielded conflicting results, and there is no consensus on interactions between alcohol and HPV-16 (the main responsible HPV subtype in head and neck cancer). ^3,10

Prevention and risk reduction

Public health strategies 

Currently, in the UK, the Chief Medical Officer’s guidelines for men and women are not to regularly drink more than 14 units of alcohol per week and to spread these over 3 or more days. NICE (the National Institute for Health and Care Excellence) recommends that patients be screened for excessive drinking, if practicable, in the following situations:

• Registering new patients
• Routine health check
• Chronic disease screening (e.g. COPD, Diabetes)
• Medication reviews
• Sexual health promotion
• Treating minor injuries
• Antenatal appointments

Lifestyle changes in lowering cancer risk

Lifestyle changes that reduce the risk of head and neck cancer include the following:¹¹

• Smoking cessation
• Reducing or stopping drinking alcohol
• Early detection of HPV and vaccination
• Primary prevention of HPV-16 by vaccination
• Maintaining oral hygiene
• A diet rich in fruits and vegetables
• Lowering BMI

Protective factors

Natural antioxidants called polyphenols may protect from the oxidative stresses of acetaldehyde on DNA. These are found in the “Mediterranean diet” - rich in olive oil, fruits, vegetables and legumes - and somewhat counterintuitively in red wine, perhaps one explanation why very moderate drinkers have a lower incidence of head and neck cancers.³

Future directions

Whilst there is currently no national screening program for head and neck cancer, patients with a lump on the tongue or lip, new symptoms of a hoarse voice, pain on swallowing, neck lumps and raspy breathing (stridor) should be referred on an urgent basis to an ENT (ear, nose and throat) specialist. A 2023 German study found that the presence of HPV-E6 antibodies was associated with a 100x increase in the overall risk of oropharyngeal cancer. The authors make a case for surveillance in this high-risk group.¹² 

Summary

Excessive alcohol consumption, along with cigarette smoking (tobacco use) and infection with the HPV virus, are important causes of squamous cell head and neck cancers. Alcohol is postulated to increase cancer risk directly and via the substances it is metabolised into - acetaldehyde and acetate. These substances damage DNA, causing the “switching on” of cancer genes (oncogenes) and the “switching off” of cancer protective genes (tumour suppressor genes), as well as inhibiting processes that prevent genetic mutations and cancer, such as DNA repair and programmed cell death. The combination of cigarette smoking and heavy alcohol intake is associated with a greater risk of cancer than the addition of both factors considered alone. Strategies to inform the public about safe alcohol limits and to screen for excessive alcohol consumption are the mainstay of public health strategies to reduce alcohol consumption. The primary prevention (vaccination) and surveillance for HPV infection are also important; however, a clear interaction between alcohol abuse and HPV infection in the causation of head and neck cancers has been challenging/difficult to establish.