Radiation-induced pulmonary fibrosis

Radiation-induced pulmonary fibrosis is the late manifestation of radiation-induced lung disease and is relatively common following radiotherapy for chest wall or intrathoracic malignancies.

This article does not deal with the changes seen in the acute phase. Please refer to the article on radiation-induced lung disease for a general discussion and radiation pneumonitis for specific discussion of acute changes.

Epidemiology

For a discussion of the epidemiology of radiation-induced lung disease, please refer to the parent article: radiation-induced lung disease.

Clinical presentation

Radiation-induced pulmonary fibrosis is typically seen between 6 and 12 months following completion of radiotherapy course and can continue to progress for up to 2 years ¹.

Although the majority of patients are asymptomatic, referred symptoms include a persistent dry cough and shortness of breath ⁷.

Rarely, particularly nowadays with the new techniques of radiation therapy, the radiation-induced chronic lung injury has been described to evolve to chronic respiratory failure, pulmonary hypertension, or chronic cor pulmonale ⁷. 

Pathology

Ionising irradiation promotes damage to lung epithelium releasing inflammatory mediators that attract inflammatory cells, which in turn secret profibrotic cytokines and chemokines thereby amplifying the inflammatory response. These profibrotic mediators stimulate fibroblasts to produce extracellular matrix proteins (e.g. collagen) resulting in the excess deposition of these material ⁶. 

Radiographic features

Although changes in the lung are usually confined to the irradiated field, changes in the remainder of the lung may also on occasion be seen ¹.

Plain radiograph

Volume loss, architectural distortion, mediastinal shift, hemidiaphragm elevation, and bronchiectasis may all be seen ^5,7. In some instances, a straight edge conforming to the irradiation portal may be evident. Review of previous imaging will usually show the progression from radiation pneumonitis (hazy opacities) progressively becoming more reticular or linear with gradual loss of volume ⁵.

CT

CT not only can better delineate parenchymal changes including volume loss and bronchiectasis but often demonstrates the change restricted to the irradiated field, in geographic distribution, rather than respecting anatomical boundaries (e.g. pleural fissures) ⁷. Changes include ^1,3,5,7:

• volume loss
• linear scarring
• chronic consolidation often with air-bronchograms
  • usually having a geographic non-anatomical distribution
  • may cross fissures
• traction bronchiectasis
• hilar vascular displacement
• mediastinal shift
• pleural thickening
• ipsilateral pleural effusion

Cavitation is rarely seen in the late acute phase of the radiation-induced lung injury as a consequence of pulmonary necrosis ⁷. Infection always plays a differential to consider when they are present ^1,7. 

It should be noted however that with highly conformal radiation therapy (eg. 3D-CRT, IMRT, SBRT, and proton therapy), the shape of the irradiated field will not have straight edges or conform to the traditional conventional radiotherapy portals. As such it may be less artificial in shape and more tightly restricted to the tumour (cf. straight lines traditionally seen in conventional radiotherapy portals) ^2,7:

• scarlike pattern: characterised by a bandlike opacity in the tumour location associated with mild volume loss ⁷
• masslike pattern: characterised by a focal consolidation/groundglass in the tumour region, with or without air bronchograms or traction bronchiectasis ⁷

MRI

Although MRI may have a role helping to distinguish malignancy from fibrosis, care must be taken in interpreting results as, granulation tissue, oedema, and areas of necrosis can all mimic tumour nodule, especially when fibrosis is also present ⁴.

Nuclear Medicine

PET-CT

FDGOnce the inflammation has receded, usually between 9 to 15 months after the completion date, FDG-PET is useful in differentiating radiation fibrosis from recurrent or radiation-induced malignancy, as the former will not be metabolically active ^1,6.

Bear in mind that FDG avidity may still beis usually present inuntil late phases of radiation pneumonitis (3 to 9 months after treatment completion) due to the presence of residual inflammation, therefore, PET-CT is of equivocal clinical value in these periodsthis period ⁷.   

Treatment and prognosis

When fibrosis has become established, no treatment is available, other than a follow-up to assess for tumour recurrence.

Differential diagnosis

If a clear demarcation conforming to the irradiation port is seen, then there is often little difficulty in making the diagnosis, especially when a history of chest radiotherapy is known.

A knowledge of the time course of the changes with respect to radiotherapy, total dose administered, administration of chemotherapy, and shape of the portal used can all have a significant impact on the differential, and thus should be sought if the referring clinician has not provided them⁷. With the highly conformal radiation therapies, any further increase in size or bulkiness of the residual scarlike or masslike patterns in the treated area is concerning for recurrent disease. 

Differential includes:

• other causes of pulmonary fibrosis
• other causes of bronchiectasis
• tuberculosis (especially in cases where the lung apices have been irradiated)
• recurrent or radiation-induced malignancy:
  • may be difficult to distinguish from scarring / late phase consolidation
  • follow-up will show malignancy to increase in size
  • involvement of chest wall or bone or lymph node increase may be presentin-field recurrence usually happen within 3 years after the completion date ³⁷
  • increase in the size of the treated area scarlike or masslike pattern of fibrosis
    • bear in mind that the post-radiation fibrotic changes usually happen around 9 months but can be seen in up to 2 years after treatment completion ⁷
    • malignancy often lack air-bronchograms and has convex outer border ^1,3
    • involvement of chest wall, bone, or lymph node increase may be present 3
  • FDG-PET/CT is useful as it will demonstrate increased metabolic activity in malignancies ¹
    • false-positive FDG uptake in some inflammation areas may occur ⁷