Introduction 

Pulmonary fibrosis is a condition in which the lung tissue, particularly the tiny air sacs called alveoli, becomes scarred and damaged over time. This scarring thickens the tissue, reducing the available space in the lungs and making it harder for them to function properly. This results in a change in lung functionality, reducing the lungs ability to efficiently diffuse gas, such as oxygen and carbon dioxide, through the membrane which can lead to hypoxemia.

When there is long term damage to the tissue, and persistent inflammation, this can lead to DNA damage in the cells; a risk associated with cancer, but can pulmonary fibrosis directly cause cancer?

What causes pulmonary fibrosis?

There are five main causes of pulmonary fibrosis:³

• Drugs - Use of drugs that specifically affect the lungs
• Radiation - caused by therapeutic radiation directed to the chest
• Environmental - obtained from exposure to animals or mould or other provoking agents
• Autoimmune - any disease causing your own immune system to attack yourself
• Occupational - Exposure to hazardous material such as dust, fibres, fumes or vapours 
• Idiopathic - Spontaneously occurs. When there is no identifiable cause.

Idiopathic pulmonary fibrosis is the most common type of pulmonary fibrosis, with approximately 50,000 new cases every year and symptoms presenting mostly in people who are 50-70 years old.⁴

Symptoms

Symptoms of pulmonary fibrosis include:

• Shortness of breath
• A constant dry cough
• Fatigue
• Loss of appetite and weight loss
• Swollen fingertips

Shortness of breath is common and is usually a normal experience, but it is not normal if it's caused by a light activity, such as getting dressed.

Diagnosis

To diagnose pulmonary fibrosis, both clinical evaluations and diagnostics testing are required:

• Medical history: Your healthcare professional will ask specific questions about your medical history and question if there are other factors that could be causing an issue with your lungs. These could be if you were previously a smoker or a current one, whether you have been exposed to harmful substances or if you have other medical conditions that can affect your breathing
• Physical examination:
  • Using a stethoscope the doctor will check the sound of your breathing. An indication of lung fibrosis would be hearing a crackling noise
  • Examine your fingers for any signs of swelling, known as finger clubbing
  • Test if you become breathless after walking around for a few minutes
• Imaging and further tests: 
  • Lung function tests can be used to assess how efficient your lungs work
  • For imaging, chest X-rays and CT scans may also be utilised
  • A narrow tube with a camera inserted into your airways, known as a bronchoscopy, can be used to identify any abnormalities
  • If the other test results are inconclusive, a lung biopsy would be carried out, involving extracting a small lung tissue sample for further analysis¹ 

Characteristics of cellular damage from pulmonary fibrosis include the “honeycomb” effect on the alveolar walls, appearing as cystic air spaces lined by fibrous tissue.²

Treatment

There is currently no known treatment that can stop or reverse the damage caused by scarring of the lungs. However, there are methods you can implement to stay healthy such as:

• Stopping smoking
• Exercising regularly 
• Eating a healthy diet
• Avoid contracting a chest infection or cold if possible

Medication that  slow the progression of idiopathic pulmonary fibrosis include:

• Pirfenidone - Helps slow down the scarring process by reducing the immune system activity
• Nintedanib - Also slows down the scarring of the lungs through blocking cancer growth via inhibiting protein kinases

In addition, oxygen therapy using an oxygen machine can help with temporarily making you feel less breathless. Pulmonary rehabilitation is also available to help with coping with the symptoms.

The relationship between pulmonary fibrosis and lung cancer

Previous studies have shown that the cumulative incidence rates of lung cancer in patients with idiopathic pulmonary fibrosis increase over time, rising from 3.3% at 1 year, to 15.4% at 5 years, and reaching 54.7% at 10 years after diagnosis.⁵ The overall incidence rate of lung cancer has been recorded as high, with an estimated rate of 13.54%,⁶ and it was notably more common in men than in women. Lung cancer in these patients is primarily found in the peripheral areas of the lung, particularly in the lower lobe.⁷ Among the different types of lung cancer, squamous cell carcinoma was the most common (37.8%), followed by adenocarcinoma (30.8%).⁸

Prognosis 

The general prognosis for idiopathic pulmonary fibrosis is unfortunately poor, with an average life expectancy of 2 to 3 years from the time of diagnosis.⁹

However, prognosis for people with both idiopathic pulmonary fibrosis and lung cancer are generally linked to a worse prognosis and a lower survival rate compared to someone who does not have cancer but has idiopathic pulmonary fibrosis. This is because they would have more severe symptoms and poorer respiratory outcomes.^10,11

Shared genetic and molecular pathways

The cytokine Tumour growth factor beta (TGF-β), could be the culprit for the link between pulmonary fibrosis and lung cancer. This is because, in a healthy environment, this growth factor is crucial for formation of alveolar structure and alveolar epithelial cell differentiation, lung homeostasis, branching morphogenesis, fibroblast activation and extracellular matrix organisation.¹²

TGF-β is found to be the most potent factor to induce fibroblast to myofibroblast differentiation,¹² which triggers the production of excess extracellular matrix components such as collagen for wound healing. Increase of collagen secretion and lack of collagen degradation causes an accumulation of collagen that hardens over time and accelerates the scarring process.¹³ Fibroblast activation to myofibroblasts occurs after recurrent epithelial tissue injury and prolonged inflammation, acting as a key step to development of fibrosis.^14,15 When the expression of this growth factor is increased, the remodelling properties are also increased and an array of regulated pathways and functions become unregulated. For instance, excessive extracellular matrix accumulation results in irreversible structural alterations and tissue stiffening of the lungs. Further alterations include promoting invasiveness and metastasis through inducing epithelial-to-mesenchymal transition (EMT), favourable characteristics for a cancer cell. 

Alterations in the expression of the tumour suppressor gene, p53 or TP53, has also been linked to carcinomas of the lung,^16,17 with individuals who had idiopathic pulmonary fibrosis showed a higher rate of expression and evidence of mutation of the p53 gene.¹⁸ In this case, it acts to promote pulmonary fibrosis via inducing alveolar epithelial cell apoptosis, oxidative stress and cellular ageing,¹⁹ enhancing further progression of fibrosis and damage to the lung cells. 

Since p53 is triggered when there is DNA damage, repeated epithelial damage and chronic inflammation that leads to oxidative stress activates this gene. Initially, p53 helps to promote repairing damaged DNA, but as the disease progresses, the oxidative stress accumulates and then under severe stress p53 enhances oxidative stress and stimulates cell death.²⁰ These changes can impair its tumour suppressing function, potentially allowing mutated cells to avoid apoptosis. If mutations arise in the p53 gene, cells with damaged DNA will continuously divide, increasing genetic mutations that can lead to cancer progression. 

These characteristics can accelerate tumour cellular growth and create a tumour microenvironment for the tumour to thrive in, thus increasing the risk of developing lung cancer.

Conclusion

There are many factors that can cause both pulmonary fibrosis and lung cancer, so it is unclear whether pulmonary fibrosis can cause lung cancer by itself. These risk factors for lung cancer in idiopathic pulmonary fibrosis are smoking, being male and ageing.²¹

Another limitation is that it's hard to distinguish lung cancer in fibrotic lung tissue as well, due to the alteration in the lungs structure from the damage and scarring that has occurred.

Even so, there is enough evidence to suggest that pulmonary fibrosis can contribute to the risk of lung cancer through affected signalling pathways, chronic damage to the tissue and creation of the ideal tumour microenvironment. However, more research should be done involving studies accounting for these risk factors to determine whether the increase in lung cancer prevalence is due to pulmonary fibrosis alone.