DOI: 10.1148/rg.244035160
RadioGraphics 2004;24:985-997
© RSNA, 2004
Effects of Radiation Therapy on the Lung: Radiologic Appearances and Differential Diagnosis1
Yo Won Choi, MD,
Reginald F. Munden, MD,
Jeremy J. Erasmus, MD,
Kyung Joo Park, MD,
Woo Kyung Chung, MD,
Seok Chol Jeon, MD and
Choong-Ki Park, MD
1 From the Department of Radiology, College of Medicine, Hanyang University, Seoul, Korea (Y.W.C., W.K.C., S.C.J., C.K.P.); the Department of Radiology, University of Texas M.D. Anderson Cancer Center, Houston (R.F.M., J.J.E.); and the Department of Radiology, Ajou University Medical Center, Suwon, Korea (K.J.P.). Presented as an education exhibit at the 2002 RSNA scientific assembly. Received July 7, 2003; revision requested August 25 and received October 9; accepted October 13. Supported in part by grant HY2002–1 from the research fund of Hanyang University. All authors have no financial relationships to disclose. Address correspondence to Y.W.C., Department of Radiology, Hanyang University Hospital, 17 Haengdang-dong, Sungdong-ku, Seoul 133–792, Korea (e-mail: ywchoi@hanyang.ac.kr).
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Abstract
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Radiation-induced lung disease (RILD) due to radiation therapy is common. Radiologic manifestations are usually confined to the lung tissue within the radiation port and are dependent on the interval after completion of treatment. In the acute phase, RILD typically manifests as ground-glass opacity or attenuation or as consolidation; in the late phase, it typically manifests as traction bronchiectasis, volume loss, and scarring. However, the use of oblique beam angles and the development of newer irradiation techniques such as three-dimensional conformal radiation therapy can result in an unusual distribution of these findings. Awareness of the atypical manifestations of RILD can be useful in preventing confusion with infection, recurrent malignancy, lymphangitic carcinomatosis, and radiation-induced tumors. In addition, knowledge of radiologic findings that are outside the expected pattern for RILD can be useful in diagnosis of infection or recurrent malignancy. Such findings include the late appearance or enlargement of a pleural effusion; development of consolidation, a mass, or cavitation; and occlusion of bronchi within an area of radiation-induced fibrosis. A comprehensive understanding of the full spectrum of these manifestations is important to facilitate diagnosis and management in cancer patients treated with radiation therapy.
© RSNA, 2004
Index Terms: Lung, effects of irradiation on, 60.47 • Lung neoplasms, therapeutic radiology, 60.1299, 60.32 • Radiations, injurious effects, complications of therapeutic radiology, 60.47
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LEARNING OBJECTIVES FOR TEST 2
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After reading this article and taking the test, the reader will be able to:
- Identify the typical radiologic manifestations of radiation-induced lung disease.
- Describe atypical or unexpected manifestations that can occur with oblique or complex irradiation techniques.
- Discuss radiologic differentiation of radiation-induced lung disease from infection or recurrent malignancy.
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Introduction
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Injury to the lung is common after therapeutic irradiation of intrathoracic and chest wall malignancies. Radiologic manifestations of radiation-induced lung disease (RILD), including ground-glass opacities or consolidation in the acute phase and traction bronchiectasis, volume loss, and consolidation in the late phase, are well described in the literature (Fig 1) (1–17). However, recent advances in irradiation techniques can produce radiologic manifestations of RILD that are not typical. Knowledge of the expanded spectrum of these manifestations is important to facilitate diagnosis and treatment of patients after radiation therapy for intrathoracic malignancies. In fact, a comprehensive understanding is essential if local recurrence of malignancy, lymphangitic carcinomatosis, radiation-induced tumors, and infections are to be differentiated from RILD.
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Figure 1a. Temporal evolution of RILD in a 60-year-old woman with stage IIIb non-small cell lung cancer. (a) Chest radiograph obtained before treatment shows a nodule in the left lung (arrow) and hilar adenopathy. (b) Chest radiograph obtained 2 months after completion of radiation therapy shows radiation pneumonitis, which manifests as faint areas of increased opacity within the radiation portal. (c) Chest radiograph obtained 9 months after completion of radiation therapy shows evolution to radiation fibrosis, which manifests as increasing volume loss and consolidation. Note the sharp demarcation between the normal and irradiated lung parenchyma.
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Figure 1b. Temporal evolution of RILD in a 60-year-old woman with stage IIIb non-small cell lung cancer. (a) Chest radiograph obtained before treatment shows a nodule in the left lung (arrow) and hilar adenopathy. (b) Chest radiograph obtained 2 months after completion of radiation therapy shows radiation pneumonitis, which manifests as faint areas of increased opacity within the radiation portal. (c) Chest radiograph obtained 9 months after completion of radiation therapy shows evolution to radiation fibrosis, which manifests as increasing volume loss and consolidation. Note the sharp demarcation between the normal and irradiated lung parenchyma.
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Figure 1c. Temporal evolution of RILD in a 60-year-old woman with stage IIIb non-small cell lung cancer. (a) Chest radiograph obtained before treatment shows a nodule in the left lung (arrow) and hilar adenopathy. (b) Chest radiograph obtained 2 months after completion of radiation therapy shows radiation pneumonitis, which manifests as faint areas of increased opacity within the radiation portal. (c) Chest radiograph obtained 9 months after completion of radiation therapy shows evolution to radiation fibrosis, which manifests as increasing volume loss and consolidation. Note the sharp demarcation between the normal and irradiated lung parenchyma.
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In this article, we review the typical radiologic manifestations of RILD and emphasize unexpected or atypical manifestations that can occur when irradiation techniques such as three-dimensional (3D) conformal irradiation are used to treat patients with malignancy. Specific topics discussed are histopathologic features and clinical factors influencing the radiologic appearance, radiologic manifestations of conventional radiation therapy, radiation therapy techniques, and differential diagnosis.
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Histopathologic Features and Clinical Factors Influencing the Radiologic Appearance
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The histopathologic response of the lungs to radiation injury is limited and manifests radiologically as two distinct patterns. To describe these patterns of RILD, the last day that radiation therapy is administered is used as a reference point for dating the changes. Typically, there is early, transient radiation pneumonitis that occurs within 4–12 weeks after completion of radiation therapy. Radiation fibrosis usually develops within 6–12 months after completion of radiation therapy and can progress for up to 2 years before stability occurs (18–25).
Various factors influence the degree of injury sustained by the lung after irradiation of a thoracic malignancy, including patient age, prior or concomitant chemotherapy, and irradiation technique (10,14,21,22,24,25). Three of the most important irradiation technique factors that affect injury are the volume of lung irradiated, the total dose of radiation delivered, and the fractionation of the dose. The total dose of radiation delivered is important, as radiologic manifestations of radiation pneumonitis rarely appear at doses below 20 Gy and are almost always present in patients who receive doses greater than 40 Gy (7,17,22). In addition, chemotherapeutic agents such as actinomycin D, adriamycin, bleomycin, and busulfan can potentiate the effects of radiation (26). Although steroids ameliorate radiation pneumonitis, abrupt termination of administration can unmask latent radiation injury to the lung (27).
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Radiologic Manifestations of Conventional Radiation Therapy
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The acute phase of RILD initially manifests radiologically as ground-glass opacities and/or consolidation in the irradiated port (Fig 2). Radiation pneumonitis can also manifest as nodular and focal consolidative opacities within the treatment port (Fig 3) (28,29). Although radiation pneumonitis usually occurs within the irradiated lung, radiation pneumonitis outside the treatment portals has been reported (11–13,15,30–32). Occasionally, an ipsilateral pleural effusion, often associated with atelectasis of the lung, develops at the time of radiation pneumonitis (17).
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Figure 2. Radiation pneumonitis in a 60-year-old woman with stage IIIb non-small cell lung cancer (same patient as in Fig 1). Computed tomographic (CT) scan obtained 2 months after completion of radiation therapy shows diffuse ground-glass attenuation in the left lung, a typical appearance of radiation pneumonitis.
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Figure 3a. Nodular radiation pneumonitis in a 65-year-old woman with adenocarcinoma of the left lower lobe and left hilar and mediastinal adenopathy. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 5 months after completion of radiation therapy shows a decrease in the size of the tumor and a new nodular area of increased attenuation in the left lower lobe (arrow). The nodular area of increased attenuation is due to radiation injury. (c) CT scan obtained 9 months after completion of radiation therapy shows evolution to fibrosis, with coalescence of the nodular area of increased attenuation and the residual tumor.
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Figure 3b. Nodular radiation pneumonitis in a 65-year-old woman with adenocarcinoma of the left lower lobe and left hilar and mediastinal adenopathy. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 5 months after completion of radiation therapy shows a decrease in the size of the tumor and a new nodular area of increased attenuation in the left lower lobe (arrow). The nodular area of increased attenuation is due to radiation injury. (c) CT scan obtained 9 months after completion of radiation therapy shows evolution to fibrosis, with coalescence of the nodular area of increased attenuation and the residual tumor.
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Figure 3c. Nodular radiation pneumonitis in a 65-year-old woman with adenocarcinoma of the left lower lobe and left hilar and mediastinal adenopathy. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 5 months after completion of radiation therapy shows a decrease in the size of the tumor and a new nodular area of increased attenuation in the left lower lobe (arrow). The nodular area of increased attenuation is due to radiation injury. (c) CT scan obtained 9 months after completion of radiation therapy shows evolution to fibrosis, with coalescence of the nodular area of increased attenuation and the residual tumor.
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Although the opacities of radiation pneumonitis can gradually resolve without radiologic sequelae when the injury to the lung is limited, in cases of more severe injury there is usually a progression to fibrosis (17,33). Radiation fibrosis manifests radiologically as a well-defined area of volume loss, linear scarring, consolidation, and traction bronchiectasis. Consolidation usually coalesces and typically has a relatively sharp border that conforms to the treatment portals rather than to anatomic boundaries (Fig 4) (14,17,24, 25,33). Occasionally, these findings are associated with ipsilateral displacement of the mediastinum and adjacent pleural thickening or effusion (7,10,14). With evolution of radiation fibrosis, demarcation between normal and irradiated lung parenchyma often becomes more sharply defined.
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Figure 4a. Radiation fibrosis in a 62-year-old woman with poorly differentiated non-small cell lung cancer. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 12 months after completion of radiation therapy shows radiation fibrosis. Note the bronchiectasis and volume loss and the sharp demarcation between normal lung tissue and areas of fibrosis.
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Figure 4b. Radiation fibrosis in a 62-year-old woman with poorly differentiated non-small cell lung cancer. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 12 months after completion of radiation therapy shows radiation fibrosis. Note the bronchiectasis and volume loss and the sharp demarcation between normal lung tissue and areas of fibrosis.
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Because CT is more sensitive than chest radiography in detection of RILD, homogeneous ground-glass attenuation representing diffuse, minimal, early radiation pneumonitis can be seen a few weeks after completion of radiation therapy, although the radiograph is normal (12,13,15,17). In addition, unusual treatment portals are also better delineated at CT. For example, the tangential-beam technique used in the treatment of breast carcinoma results in a characteristic CT appearance, with parenchymal increased attenuation confined to the anterolateral subpleural region of the lung (Fig 5) (34).
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Figure 5a. RILD due to tangential-beam irradiation in a 42-year-old woman with adenocarcinoma of the right breast. (a) CT scan obtained 4 months after completion of radiation therapy shows ground-glass attenuation and nodules, which are predominantly located in the peripheral aspect of the right upper lobe. (b) CT scan obtained 26 months after completion of radiation therapy shows the typical pattern of subpleural radiation fibrosis in lung tissue adjacent to the treated chest wall region.
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Figure 5b. RILD due to tangential-beam irradiation in a 42-year-old woman with adenocarcinoma of the right breast. (a) CT scan obtained 4 months after completion of radiation therapy shows ground-glass attenuation and nodules, which are predominantly located in the peripheral aspect of the right upper lobe. (b) CT scan obtained 26 months after completion of radiation therapy shows the typical pattern of subpleural radiation fibrosis in lung tissue adjacent to the treated chest wall region.
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Radiation Therapy Techniques
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To deliver an adequate or tumoricidal dose of radiation to tumors while limiting the amount of normal lung exposed, a number of methods have been developed. These include use of limited radiation portals, tangential beams, conformal therapy, and intensity-modulated radiation therapy (20,22,35). A 3D conformal irradiation technique, one of the more recent and sophisticated irradiation techniques, uses multiple radiation beams to generate dose distributions that conform tightly to target volumes. This technique ensures that the entire target volume is adequately treated while minimizing dose to normal structures. Intensity-modulated radiation therapy is a technique that delivers intensity-modulated radiation to irregularly shaped target volumes by using dynamic multileaf collimators in 3D conformal therapy. Because radiation portals and beam angles can be altered depending on the location, extent, and disease entity, RILD can vary in shape and distribution. Recognition of radiologic manifestations of complex portal arrangements such as 3D conformal therapy can be facilitated with computed dosimetric reconstruction, whereby treatment volumes are superimposed on a CT scan (Fig 6) (36).
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Figure 6a. Images obtained with computed dosimetric reconstruction. (a) Isodose line image used for planning standard anteroposterior-posteroanterior radiation therapy. The area of highest radiation dose is indicated by the magenta line around the border of the right chest wall (arrows). (b) Isodose axial image used for planning 3D conformal radiation therapy in another patient. The area of highest radiation dose is indicated by the aquamarine line immediately surrounding the tumor. With 3D radiation therapy, the highest radiation dose is delivered to the tumor; with standard radiation therapy, the highest dose is at the chest wall.
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Figure 6b. Images obtained with computed dosimetric reconstruction. (a) Isodose line image used for planning standard anteroposterior-posteroanterior radiation therapy. The area of highest radiation dose is indicated by the magenta line around the border of the right chest wall (arrows). (b) Isodose axial image used for planning 3D conformal radiation therapy in another patient. The area of highest radiation dose is indicated by the aquamarine line immediately surrounding the tumor. With 3D radiation therapy, the highest radiation dose is delivered to the tumor; with standard radiation therapy, the highest dose is at the chest wall.
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To avoid diagnostic confusion, it is important to recognize not only the use of limited tangential beams, conformal therapy, and intensity-modulated radiation therapy but also the typical irradiation techniques and portals used to treat different malignancies in the thorax (2). Non–small cell lung cancer typically has a treatment portal that encompasses the primary tumor and has an additional 2-cm margin around the visualized edge of the tumor and a 1-cm margin around treated regional lymph nodes (37). If there is an extensive mediastinal component of the tumor, the ipsilateral supraclavicular area is usually included within the irradiated volume (37). In addition, the use of complex portal arrangements can result in lung opacities at unusual locations away from the site of disease that can be mistaken for other disease entities. When non–small cell lung cancer is treated with 3D conformal irradiation, RILD can manifest as a modified conventional pattern (consolidation, volume loss, and bronchiectasis similar to but less extensive than conventional radiation fibrosis), a scarlike pattern (linear opacity in the region of the original tumor), or a masslike pattern. Although diagnostic confusion is unlikely to arise from the modified conventional and scarlike patterns, the masslike pattern can easily be misinterpreted as malignancy in the absence of a history of 3D conformal irradiation (Fig 7) (38).
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Figure 7a. Three patterns of radiation-induced lung injury after 3D conformal radiation therapy. (a-c) Modified conventional pattern in a 53-year-old woman with adenocarcinoma. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 1 month after completion of radiation therapy shows a decrease in the size of the mass along with ground-glass attenuation, which is indicative of pneumonitis. (c) CT scan obtained 5 months after completion of radiation therapy shows organization of the pneumonitis into fibrosis. Note the volume loss, consolidation, and air bronchograms, as in conventional fibrosis; however, the fibrosis is localized to a small area of the lung. (d) Masslike pattern in a 67-year-old man with squamous cell carcinoma. CT scan obtained 14 months after completion of radiation therapy shows the consolidation and bronchiectasis of fibrosis. The fibrosis forms a masslike area of increased attenuation, which could be mistaken for a malignancy. (e) Scarlike pattern in a 60-year-old woman with poorly differentiated non-small cell carcinoma. CT scan obtained 5 years after completion of radiation therapy shows only a linear band of fibrosis, which resembles a scar.
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Figure 7b. Three patterns of radiation-induced lung injury after 3D conformal radiation therapy. (a-c) Modified conventional pattern in a 53-year-old woman with adenocarcinoma. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 1 month after completion of radiation therapy shows a decrease in the size of the mass along with ground-glass attenuation, which is indicative of pneumonitis. (c) CT scan obtained 5 months after completion of radiation therapy shows organization of the pneumonitis into fibrosis. Note the volume loss, consolidation, and air bronchograms, as in conventional fibrosis; however, the fibrosis is localized to a small area of the lung. (d) Masslike pattern in a 67-year-old man with squamous cell carcinoma. CT scan obtained 14 months after completion of radiation therapy shows the consolidation and bronchiectasis of fibrosis. The fibrosis forms a masslike area of increased attenuation, which could be mistaken for a malignancy. (e) Scarlike pattern in a 60-year-old woman with poorly differentiated non-small cell carcinoma. CT scan obtained 5 years after completion of radiation therapy shows only a linear band of fibrosis, which resembles a scar.
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Figure 7c. Three patterns of radiation-induced lung injury after 3D conformal radiation therapy. (a-c) Modified conventional pattern in a 53-year-old woman with adenocarcinoma. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 1 month after completion of radiation therapy shows a decrease in the size of the mass along with ground-glass attenuation, which is indicative of pneumonitis. (c) CT scan obtained 5 months after completion of radiation therapy shows organization of the pneumonitis into fibrosis. Note the volume loss, consolidation, and air bronchograms, as in conventional fibrosis; however, the fibrosis is localized to a small area of the lung. (d) Masslike pattern in a 67-year-old man with squamous cell carcinoma. CT scan obtained 14 months after completion of radiation therapy shows the consolidation and bronchiectasis of fibrosis. The fibrosis forms a masslike area of increased attenuation, which could be mistaken for a malignancy. (e) Scarlike pattern in a 60-year-old woman with poorly differentiated non-small cell carcinoma. CT scan obtained 5 years after completion of radiation therapy shows only a linear band of fibrosis, which resembles a scar.
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Figure 7d. Three patterns of radiation-induced lung injury after 3D conformal radiation therapy. (a-c) Modified conventional pattern in a 53-year-old woman with adenocarcinoma. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 1 month after completion of radiation therapy shows a decrease in the size of the mass along with ground-glass attenuation, which is indicative of pneumonitis. (c) CT scan obtained 5 months after completion of radiation therapy shows organization of the pneumonitis into fibrosis. Note the volume loss, consolidation, and air bronchograms, as in conventional fibrosis; however, the fibrosis is localized to a small area of the lung. (d) Masslike pattern in a 67-year-old man with squamous cell carcinoma. CT scan obtained 14 months after completion of radiation therapy shows the consolidation and bronchiectasis of fibrosis. The fibrosis forms a masslike area of increased attenuation, which could be mistaken for a malignancy. (e) Scarlike pattern in a 60-year-old woman with poorly differentiated non-small cell carcinoma. CT scan obtained 5 years after completion of radiation therapy shows only a linear band of fibrosis, which resembles a scar.
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Figure 7e. Three patterns of radiation-induced lung injury after 3D conformal radiation therapy. (a-c) Modified conventional pattern in a 53-year-old woman with adenocarcinoma. (a) CT scan obtained before treatment shows a mass in the left lower lobe. (b) CT scan obtained 1 month after completion of radiation therapy shows a decrease in the size of the mass along with ground-glass attenuation, which is indicative of pneumonitis. (c) CT scan obtained 5 months after completion of radiation therapy shows organization of the pneumonitis into fibrosis. Note the volume loss, consolidation, and air bronchograms, as in conventional fibrosis; however, the fibrosis is localized to a small area of the lung. (d) Masslike pattern in a 67-year-old man with squamous cell carcinoma. CT scan obtained 14 months after completion of radiation therapy shows the consolidation and bronchiectasis of fibrosis. The fibrosis forms a masslike area of increased attenuation, which could be mistaken for a malignancy. (e) Scarlike pattern in a 60-year-old woman with poorly differentiated non-small cell carcinoma. CT scan obtained 5 years after completion of radiation therapy shows only a linear band of fibrosis, which resembles a scar.
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In patients with small cell lung cancer, two types of radiation portals can be used: (a) extensive portals encompassing the hila, the mediastinum, and both supraclavicular areas and (b) limited portals encompassing only the primary tumor and adjacent nodal stations with a high likelihood of neoplastic involvement (37). In patients with breast cancer, use of tangential-beam radiation portals may induce RILD at the periphery of the lung (Fig 5). This fibrosis is better visualized on CT scans than on radiographs (13,34). To avoid confusion with infection such as tuberculosis, it is important to know that supraclavicular portals are also occasionally used in breast cancer patients and will often result in apical RILD (Fig 8).
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Figure 8a. Apical RILD due to supraclavicular radiation therapy in a 42-year-old woman with adenocarcinoma of the right breast (same patient as in Fig 5). (a) CT scan obtained 4 months after completion of radiation therapy shows ground-glass attenuation and nodular areas of increased attenuation in the right upper lobe, findings indicative of radiation pneumonitis. (b) CT scan obtained 16 months after completion of radiation therapy shows organization of the apical radiation pneumonitis into fibrosis.
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Figure 8b. Apical RILD due to supraclavicular radiation therapy in a 42-year-old woman with adenocarcinoma of the right breast (same patient as in Fig 5). (a) CT scan obtained 4 months after completion of radiation therapy shows ground-glass attenuation and nodular areas of increased attenuation in the right upper lobe, findings indicative of radiation pneumonitis. (b) CT scan obtained 16 months after completion of radiation therapy shows organization of the apical radiation pneumonitis into fibrosis.
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In patients with esophageal cancer, radiation portals with a 5–6-cm margin above and below the tumor are generally used. The radiation beams are angled to limit radiation exposure of the spinal cord and result in paramediastinal opacities in the lower lobes (Fig 9). Radiation therapy for head and neck cancer patients often includes the apical aspect of the thorax and results in bilateral apical RILD (Fig 10). The mantle field used for definitive radiation therapy of Hodgkin or non-Hodgkin lymphomas includes all the major lymph node regions above the diaphragm (39,40) and results in a classic appearance of radiation pneumonitis and fibrosis in the paramediastinal areas and in the apices (Fig 11).
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Figure 9. RILD after adjuvant chemotherapy and radiation therapy in a 53-year-old man with adenocarcinoma of the distal esophagus. CT scan obtained 3 months after completion of therapy shows areas of increased attenuation, a finding consistent with early radiation fibrosis. The RILD is more prominent in the left lower lobe but is bilateral and has the typical paramediastinal distribution.
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Figure 10a. Biapical RILD in a 72-year-old woman with squamous cell carcinoma of the tonsil. (a) Chest radiograph shows bilateral apical radiation fibrosis and pleural thickening. (b) CT scan shows radiation fibrosis in the lung apices. The distribution and appearance are typical of RILD in patients with head and neck cancer.
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Figure 10b. Biapical RILD in a 72-year-old woman with squamous cell carcinoma of the tonsil. (a) Chest radiograph shows bilateral apical radiation fibrosis and pleural thickening. (b) CT scan shows radiation fibrosis in the lung apices. The distribution and appearance are typical of RILD in patients with head and neck cancer.
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Figure 11a. Paramediastinal RILD in a 27-year-old woman with nodular sclerosing Hodgkin lymphoma. (a) CT scan obtained with narrow window settings (level, –675 HU; width, 750 HU) 16 weeks after completion of radiation therapy shows subtle paramediastinal ground-glass attenuation in the upper lobes, a finding indicative of radiation pneumonitis. (b) CT scan obtained 11 months after completion of radiation therapy shows organization of the radiation pneumonitis into the typical paramediastinal pattern of fibrosis.
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Figure 11b. Paramediastinal RILD in a 27-year-old woman with nodular sclerosing Hodgkin lymphoma. (a) CT scan obtained with narrow window settings (level, –675 HU; width, 750 HU) 16 weeks after completion of radiation therapy shows subtle paramediastinal ground-glass attenuation in the upper lobes, a finding indicative of radiation pneumonitis. (b) CT scan obtained 11 months after completion of radiation therapy shows organization of the radiation pneumonitis into the typical paramediastinal pattern of fibrosis.
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Differential Diagnosis
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Patients with thoracic malignancies treated with radiation can develop RILD as well as superimposed lung disease. Diagnosis requires a high index of suspicion because infection and recurrence of the underlying malignancy can manifest clinically and radiologically in a similar manner (41). Differentiation from RILD is often difficult but is important in determining appropriate therapy. Knowledge of the temporal relationship of radiologic manifestations to initiation and completion of radiation therapy as well as the radiation dose given can be useful in suggesting the diagnosis. In general, patients who have received more than 40 Gy of radiation should be suspected of having radiation pneumonitis if the radiologic manifestations occur within the radiation portal and within an appropriate time course. However, because RILD can be affected by the patient’s age and synergism with other drugs, more rapid onset does not exclude RILD, especially if there has been treatment with chemotherapeutic agents. When radiologic manifestations atypical for RILD are observed, the possibility of infection, locally recurrent neoplasm, lymphangitic carcinomatosis, and radiation-induced neoplasms should be considered (14,28,29,42,43).
Review of chest radiographs and CT scans at initiation of, during, and after therapy will often be useful in differentiation. For instance, infection should be considered if the chest radiograph shows pulmonary opacities occurring prior to completion of therapy or outside of the radiation portal (Fig 12). Because radiation pneumonitis normally has a more indolent course than an infectious pneumonitis, an abrupt onset is suspicious for an infection (unless there has been recent discontinuation of steroid therapy), and appropriate diagnostic and therapeutic steps should be initiated (41). Additional findings can also suggest the presence of infection. For example, RILD in the lung apices corresponding to the supraclavicular portals may be confused with pulmonary tuberculosis that has been reactivated by radiation (17). In these cases, CT findings of centrilobular nodules or branching linear structures ("tree-in-bud" appearance) are more likely due to tuberculosis than to RILD (44). Cavitation within an area of radiation fibrosis generally represents superimposed infection (9).
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Figure 12a. Pulmonary infection in a 52-year-old man with poorly differentiated non-small cell lung cancer being treated with 3D conformal radiation therapy. (a) CT scan obtained before treatment shows a large mass in the left lower lobe. (b) CT scan obtained 12 weeks after completion of radiation therapy shows numerous poorly defined nodules outside the radiation treatment port. Although the CT appearance mimics that of metastatic nodules, a unilateral distribution would be atypical.
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Figure 12b. Pulmonary infection in a 52-year-old man with poorly differentiated non-small cell lung cancer being treated with 3D conformal radiation therapy. (a) CT scan obtained before treatment shows a large mass in the left lower lobe. (b) CT scan obtained 12 weeks after completion of radiation therapy shows numerous poorly defined nodules outside the radiation treatment port. Although the CT appearance mimics that of metastatic nodules, a unilateral distribution would be atypical.
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Local tumor recurrence can be difficult to diagnose during the evolution of RILD. However, as RILD stabilizes, alteration in the contour of the fibrosis should raise the suspicion of tumor recurrence. Parenchymal consolidation with a straight lateral margin and air bronchograms is typical for radiation fibrosis, whereas a homogeneous opacity without air bronchograms and with a convex border is strongly suggestive of recurrent tumor in the irradiated lung (Fig 13) (43). In addition, filling in of bronchi within radiation fibrosis is abnormal and usually represents local recurrent malignancy or a superimposed infection (Fig 14). Lymphangitic carcinomatosis can mimic RILD; however, the extent of dyspnea, particularly in the early stages, is usually out of proportion to the extent of radiologic involvement (17,45). The characteristically rapid, inexorable progression of clinical symptoms and radiologic manifestations (septal lines, ground-glass opacities, pleural effusions) will often allow a confident diagnosis of lymphangitic carcinomatosis. Other signs of local recurrence include nodules developing outside of radiation fibrosis, pleural effusion long after completion of treatment, bone destruction, irregularity of central airways, contralateral deviation of the trachea, and diaphragmatic elevation due to phrenic nerve invasion by an aortico-pulmonary window mass.
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Figure 13a. Recurrent tumor in a 68-year-old woman with stage IIIb adenocarcinoma of the right upper lobe. (a) CT scan obtained 15 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. (b) CT scan obtained 20 months after completion of radiation therapy shows that the fibrosis has developed a convex contour, a finding indicative of recurrent tumor.
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Figure 13b. Recurrent tumor in a 68-year-old woman with stage IIIb adenocarcinoma of the right upper lobe. (a) CT scan obtained 15 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. (b) CT scan obtained 20 months after completion of radiation therapy shows that the fibrosis has developed a convex contour, a finding indicative of recurrent tumor.
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Figure 14a. Recurrent tumor in a 61-year-old woman after chemotherapy and radiation therapy for a large cell carcinoma of the right upper lobe. (a) CT scan obtained 7 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. (b) CT scan obtained 11 months after completion of radiation therapy shows soft tissue filling the bronchi (arrows), a finding indicative of recurrent tumor.
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Figure 14b. Recurrent tumor in a 61-year-old woman after chemotherapy and radiation therapy for a large cell carcinoma of the right upper lobe. (a) CT scan obtained 7 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. (b) CT scan obtained 11 months after completion of radiation therapy shows soft tissue filling the bronchi (arrows), a finding indicative of recurrent tumor.
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Chest radiography, CT, and magnetic resonance (MR) imaging may not allow differentiation of residual or recurrent malignancy from RILD. Positron emission tomography (PET) performed with the radiopharmaceutical 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) allows distinction of metabolically active tumor from metabolically inactive fibrosis after radiation therapy and may have a role in evaluation of patients with RILD (46–54) (Figs 15, 16). In our experience, the high negative predictive value of a normal FDG PET study in patients with RILD is clinically useful, and focal pulmonary opacities with low FDG uptake can be followed radiologically. Although increased FDG uptake in the irradiated lung is suggestive of malignancy, a limitation of PET imaging is that false-positive uptake of FDG is not uncommon early after completion of radiation therapy. Because radiation pneumonitis can have increased FDG uptake that mimics recurrent disease, FDG PET is best performed at least 3 months after completion of radiation therapy. Although CT, MR imaging, and PET often allow differentiation of recurrent tumor from radiation fibrosis, there are instances when definitive diagnosis with invasive procedures such as bronchoscopy, percutaneous needle aspiration biopsy, open lung biopsy, or thoracentesis is required (55–59) (Fig 15).
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Figure 15a. Radiation fibrosis in a 53-year-old man with squamous cell carcinoma of the right upper lobe. (a) Chest radiograph obtained 8 months after completion of radiation therapy shows that the right hilum has an abnormal contour. There was concern that this contour represented recurrent tumor. (b) CT scan shows a right lower lobe mass that abuts the hilum (arrow). (c) PET scan shows normal FDG uptake in the thorax. (d) Fused CT-PET scan shows normal activity in the mass, thus confirming the absence of recurrent tumor in the area of radiation fibrosis.
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Figure 15b. Radiation fibrosis in a 53-year-old man with squamous cell carcinoma of the right upper lobe. (a) Chest radiograph obtained 8 months after completion of radiation therapy shows that the right hilum has an abnormal contour. There was concern that this contour represented recurrent tumor. (b) CT scan shows a right lower lobe mass that abuts the hilum (arrow). (c) PET scan shows normal FDG uptake in the thorax. (d) Fused CT-PET scan shows normal activity in the mass, thus confirming the absence of recurrent tumor in the area of radiation fibrosis.
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Figure 15c. Radiation fibrosis in a 53-year-old man with squamous cell carcinoma of the right upper lobe. (a) Chest radiograph obtained 8 months after completion of radiation therapy shows that the right hilum has an abnormal contour. There was concern that this contour represented recurrent tumor. (b) CT scan shows a right lower lobe mass that abuts the hilum (arrow). (c) PET scan shows normal FDG uptake in the thorax. (d) Fused CT-PET scan shows normal activity in the mass, thus confirming the absence of recurrent tumor in the area of radiation fibrosis.
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Figure 15d. Radiation fibrosis in a 53-year-old man with squamous cell carcinoma of the right upper lobe. (a) Chest radiograph obtained 8 months after completion of radiation therapy shows that the right hilum has an abnormal contour. There was concern that this contour represented recurrent tumor. (b) CT scan shows a right lower lobe mass that abuts the hilum (arrow). (c) PET scan shows normal FDG uptake in the thorax. (d) Fused CT-PET scan shows normal activity in the mass, thus confirming the absence of recurrent tumor in the area of radiation fibrosis.
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Figure 16a. Recurrent tumor in a 60-year-old woman with limited small cell carcinoma. (a) CT scan obtained 27 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. Note the patent air bronchogram. (b) Fused CT-PET scan shows increased FDG uptake in the area of fibrosis. Note that the recurrent tumor does not fill in the air bronchogram.
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Figure 16b. Recurrent tumor in a 60-year-old woman with limited small cell carcinoma. (a) CT scan obtained 27 months after completion of radiation therapy shows radiation fibrosis in the right upper lobe. Note the patent air bronchogram. (b) Fused CT-PET scan shows increased FDG uptake in the area of fibrosis. Note that the recurrent tumor does not fill in the air bronchogram.
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Conclusions
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RILD is common after radiation therapy of thoracic malignancies, and radiologic manifestations typically have a characteristic temporal relationship to the completion of therapy. However, radiologic manifestations of RILD can vary according to the radiation therapy technique used. Knowledge of this temporal relationship and an understanding of the expected patterns of radiation pneumonitis and fibrosis associated with different radiation therapy techniques are needed to suggest a diagnosis of RILD and to differentiate RILD from recurrent tumor or superimposed infection.
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Footnotes
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Abbreviations: FDG = 2-[F-18]fluoro-2-deoxy-D-glucose,
RILD = radiation-induced lung disease,
3D = three-dimensional
See the commentary by Marks
following this article.
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References
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Abstract
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