Introduction

Tubular adenomas are benign (non-cancerous) protrusions which form from the colon's mucosa (the inner lining), formed by glandular tissue. Although they are non-cancerous, in some cases (less than 10% of cases), they can be considered pre-cancerous. Hence, it is important to understand the pathogenesis and signs to reduce any risk and rule out the possibility of it being cancerous and/or treat it at its earliest.^1,2

This article addresses the pathogenesis of tubular adenoma as well as provides an overview of what tubular adenoma is. 

Overview of tubular adenoma

Tubular adenomas are one of the most common types of colonic polyps diagnosed during routine colonoscopies. Adenomas in general are primarily located in the region of the colon that reaches the rectum (colorectal area). Patients are mostly asymptomatic; however, some warning signs could be:

• Constipation or diarrhoea 
• Bright or dark red blood when wiping after opening your bowels (no pain) 
• Loss of appetite 
• Stomach pain^1,2

Tubular adenomas are characterised by distinct histological and morphological features that play a critical role in their classification and clinical significance. When examined under a microscope, tubular adenomas grow in a pattern resembling up and down squiggly lines or tubes, but in an orderly way.^1,2 To delve deeper into the histology of tubular adenoma, when examined, the nuclei (part of the cell that contains all the cell's DNA) are enlarged, and there is increased mitotic activity. This means that more and more cells are dividing.³

The amount of dysplasia (the amount of abnormal cell growth) can also indicate how much the polyp looks like cancer. A low abnormality is said to have low-grade dysplasia, whereas those that look more abnormal are said to have high-grade dysplasia and appear more like cancer.⁴ Fortunately, the process of tubular adenomas turning cancerous takes years, and through the help of regular colonoscopies, they can be detected and removed before becoming so.⁵ Although tubular adenomas have a smaller risk of becoming cancerous, they still have the potential to form carcinomas (a type of cancer). This develops through the adenoma-carcinoma sequence (ACS). The ACS is a series of mutations that lead to cancer formation, normally through the inactivation of certain tumour suppressor genes (a gene that regulates cell division). 

Many genetic and environmental factors play a part in tubular adenoma pathogenesis, which will be discussed in this article. 

Genetic factors in tubular adenoma pathogenesis

Genetic factors play a crucial role in the pathogenesis of tubular adenomas, influencing their progression and potential transformation into colorectal cancer. Key factors include genetic mutations, much like what is responsible for the adenoma-carcinoma sequence (ACS), epigenetic changes, as well as hereditary syndromes. 

Genetic mutations

Genetic mutations, as mentioned previously, play a fundamental role in adenoma formation as they serve as the initial trigger of the adenoma-carcinoma sequence. An example of a mutation that occurs is the mutation in the APC gene. The APC gene is a tumour suppressor gene responsible for regulating cell growth, so when mutated, it affects a cell signalling pathway known as the Wnt signalling pathway. Thus, it leads to uncontrolled cell growth (proliferation), which contributes to adenoma formation.^6,7 Another that may occur is a mutation in the KRAS gene, which can promote tumour formation as it prevents apoptosis (programmed cell death) and enables further cell proliferation.⁸ These genetic factors can be studied upon tubular adenoma resection to indicate any pre-cancerous markers.² 

Epigenetic changes

Epigenetic changes also play a significant role in the pathogenesis of tubular adenomas. Epigenetic changes are modifications that affect the way that genes are expressed without altering the DNA sequence itself. So, in other words, certain genes can be switched on or off, which then changes the way your body reads them. One key mechanism is DNA methylation, in particular the hypermethylation of tumour suppressor genes. This means that certain protective genes that are normally expressed to halt proliferation are switched off, leading to increased cell proliferation.⁹ In addition to adenoma formation, the accumulation of these changes can lead to the progression of colorectal cancer.¹⁰ 

Familial and hereditary syndromes

Linking back to genetic mutations, the formation of tubular adenomas may be due to inherited genetic changes. For example, familial adenomatous polyposis (FAP) which predisposess you to develop tubular adenomas. If left untreated, the risk of colon cancer is also slightly higher, as you develop many adenomas as you age.^2,11

Environmental factors in tubular adenoma pathogenesis

While genetic factors play a key role in the development of tubular adenomas, environmental influences also contribute to their formation and progression. Lifestyle choices, dietary habits, and the gut microbiome can either increase the risk of adenoma development or, conversely, help protect against it. These factors often interact with genetic predispositions, amplifying or mitigating the impact of inherited mutations.  

Diet

The food you consume plays a significant role in the development of tubular adenomas, with certain foods increasing the risk of their formation. To elaborate, data obtained in a study conducted by Ferrucci et al. found that those who had a high consumption of red meat and processed meats had an elevated risk of tubular adenomas as well as other colorectal adenomas. This may be due to the foods providing a more favourable environment for inflammation and oxidative stress, promoting cellular damage and adenoma formation.¹² In contrast, diets that are rich in fruits, vegetables and whole grains were shown to offer a protective effect, which may in turn lower the risk of tubular adenoma formation.¹³ 

Lifestyle and behavioural factors

Lifestyle and behavioural changes also affect the development of tubular adenomas. Like many conditions, smoking and alcohol consumption may play a part. Studies found that excessive alcohol consumption has been linked to adenoma formation as it impairs DNA repair mechanisms and promotes an inflammatory environment. As well as this, smoking has been strongly associated with an increased risk of adenoma formation, as it introduces carcinogenic compounds that can induce both genetic and epigenetic changes.^14,15 

Microbiota and inflammation

A common theme arising from these factors is the prevalence of increased inflammation, which causes changes in the DNA of cells in the colon, leading to tubular adenoma formation. The inflammation can be increased due to an imbalance of the bacteria in the gut, otherwise known as dysbiosis. This creates a state of chronic inflammation (prolonged inflammatory state), which can further harm the colon, leading to the formation of adenomas.^16,17 Additionally, in the instances that it may turn cancerous, the chronic inflammation that is promoted by these changes favours the tumour microenvironment, facilitating the transition from adenoma to carcinoma.¹⁸ 

All in all, both genetic and environmental factors play a role in the pathogenesis of tubular adenomas as well as their potential to form cancer. It is also worth noting that these can have a synergistic effect (combined effect) on each other, leading to the formation of tubular adenomas.¹⁹

Preventative and therapeutic implications

Through understanding the pathogenesis of tubular adenomas, we are able to have insight into preventative measures we can take as well as potential therapeutic targets. The primary treatment method for tubular adenomas is the removal, where it can then be examined for its cellular properties.² Preventative measures could include:

• Maintaining a healthy diet, such as foods that are high in fibre and reducing the amount of red meat you consume
• Limiting your alcohol consumption and trying to give up smoking
• Routine colonoscopies are also recommended to detect any more that may form

By doing so, the formation of tubular adenomas is managed and monitored effectively.  

Conclusion

To conclude, tubular adenomas are benign protrusions that, although rare, have the potential to turn cancerous. The pathogenesis of tubular adenomas is governed through genetic predisposition as well as environmental influences. These factors can work synergistically to have a greater influence on tubular adenoma formation. Genetic factors contributing to tubular adenoma pathogenesis include mutations in the APC gene as well as epigenetic modifications through DNA methylation. At the same time, lifestyle factors, including diet, smoking, alcohol consumption, and gut microbiota composition, can either exacerbate these risks. Regular colonoscopy screenings, lifestyle modifications, and emerging targeted therapies provide effective means of managing tubular adenomas and reducing their potential progression to colorectal cancer. Understanding these contributing factors allows for better risk assessment, earlier intervention, and improved therapeutic strategies, ultimately improving patient outcomes.