Introduction
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Postoperative radiotherapy is indicated for the management of breast cancer. The objective of radiotherapy for breast cancer is to minimize the risk of local or regional recurrence (Early Breast Cancer Trialists\' Collaborative Group, 2005\[[@R2]\]). Radiation injury to the lung has been described as the most important adverse consequence of radiotherapy of the lung fields (Kubo et al., 2009\[[@R9]\]). Bronchiolitis obliterans organizing pneumonia (BOOP) was recently reported to develop outside the irradiation field. We report two cases of BOOP syndrome that occurred outside the irradiated field after several months of postoperative radiotherapy for breast cancer.

Case 1
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A 66-year-old Japanese female complained of cough and sputum production for four weeks, commencing 23 weeks after receiving 50 Gy of tangential field irradiation for postoperative radiotherapy of right breast cancer. On admission to our hospital, her body temperature was 36.8 °C and oxyhemoglobin saturation was 95 % while breathing room air. Physical examination revealed a surgical scar on the right mammary gland. On auscultation, the lungs were clear and no cardiac murmurs were audible. Laboratory analyses showed increased levels of C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and surfactant protein-D (SP-D). Chest radiography and computed tomography (CT) demonstrated multiple infiltrative shadows in the upper, middle and lower lobes of the right lung field (Figures 1a-c[(Fig. 1)](#F1){ref-type="fig"}). Bacterial pathogens, including *Mycobacterium*, were not cultured from sputum. Histological findings from transbronchial lung biopsy revealed increased thickness of the alveolar walls and infiltration of lymphocytes into the alveoli. Analysis of bronchoalveolar lavage (BAL) fluid (3x50 ml from the right middle lobe) showed increased total cell counts and percentage of lymphocytes (total cells counts, 40.0×10^4^/ml; macrophages, 50.5 %; neutrophils, 7.7 %; lymphocytes, 41.7 %; eosinophils, 0 %). Consolidation on the chest radiograph moved to other lung fields two weeks after admission (Figures 1d-f[(Fig. 1)](#F1){ref-type="fig"}). BOOP syndrome was diagnosed on the basis of the clinical course and results of the examination. After treatment with 30 mg of systemic prednisolone, consolidation in the lung fields disappeared and the patient\'s symptoms improved.

Case 2
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A 65-year-old Japanese female was admitted to our hospital with pyrexia, cough and dyspnea which continued for two weeks, and commencing 26 weeks after she received 50 Gy of tangential field irradiation for postoperative radiotherapy of right breast cancer. On admission, her body temperature was 37.6 °C, and oxyhemoglobin saturation was 97 % while breathing room air. Physical examination revealed a surgical scar on the right mammary gland. On auscultation, the lungs were clear and no cardiac murmurs were audible. Laboratory analyses showed increase levels of CRP. Chest radiography and CT demonstrated multiple infiltrative shadows in the upper and lower lobes of the right lung field (Figures 2a-c[(Fig. 2)](#F2){ref-type="fig"}). Bacterial pathogens, including *Mycobacterium*, were not cultured from sputum. Histological findings from transbronchial lung biopsy revealed increased thickness of the alveolar walls and infiltration of macrophages, lymphocytes and eosinophils into the alveoli. Analysis of BAL fluid (3×50 ml, from the right middle lobe) did not show any significant findings (total cells count, 8.0×10^4^/ml; macrophages, 71.4 %; neutrophils, 7.4 %; lymphocytes, 19.8 %; eosinophils, 1.7 %). Consolidation on the chest radiograph moved to other lung fields two weeks after admission (Figures 2d-f[(Fig. 2)](#F2){ref-type="fig"}). BOOP syndrome was diagnosed on the basis of the clinical course and results of the examination. After treatment with 30 mg of systemic prednisolone, consolidation in the lung fields disappeared and the patient\'s symptoms improved.

Discussion
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In recent years, breast-conserving surgery has become standard therapy for early stage breast cancer. The rates of local recurrence, as well as mortality, are decreased if radiotherapy is administered postoperatively (Early Breast Cancer Trialists\' Collaborative Group, 2005\[[@R2]\]). It is well known that radiotherapy for thoracic cancer may induce radiation pneumonitis. This occurs in the irradiated lung fields at an early time after radiotherapy (Kubo et al., 2009\[[@R9]\]).

In 1990, Kaufman and co-worker first reported a case of BOOP that occurred one month after radiotherapy for small cell lung cancer (Kaufman and Komorowski, 1990\[[@R7]\]). Some reports suggested that radiation injury occurring outside the irradiated lung fields should be diagnosed as BOOP syndrome. BOOP is characterized by symptoms of fever, cough, infiltrative shadows in the lung, and pathologically organizing granulation tissue, with migration of inflammatory cells into the alveolar spaces. BOOP is responsive to corticosteroid therapy, but not to antibiotic therapy (Epler et al., 1985\[[@R3]\]).

The first report of BOOP syndrome after radiotherapy for breast cancer appeared in 1998 (Crestani et al., 1998\[[@R1]\]). Crestani et al. defined four criteria for radiation-induced BOOP syndrome. First, it occurs within 12 months after irradiation. Second, systemic or respiratory symptoms such as fever or cough persist for more than two weeks. Third, infiltration of the lungs occurs outside the field of irradiation. Fourth, any other cause is excluded. Using these criteria, they identified 15 cases of radiation induced BOOP syndrome. Although these 15 cases showed some characteristics of BOOP syndrome, such as respiratory or systemic symptoms, or mobile infiltration of the lung, only five cases were proven to be BOOP based on histopathological findings. However, dramatic improvement was observed when these 15 patients received corticosteroid therapy. Crestani et al. (1998\[[@R1]\]) pointed out that corticosteroid therapy would be effective in patients with radiation induced BOOP syndrome that matched their criteria, even without a histological diagnosis.

BOOP syndrome matching the criteria of Crestani et al. (1998\[[@R1]\]) reportedly occurs after radiotherapy in 2.3 to 2.5 % of breast cancer patients (Takigawa et al., 2000\[[@R12]\]; Miwa et al., 2004\[[@R10]\]; Katayama et al., 2009\[[@R6]\]). The two cases reported here matched the criteria of Crestani et al. (1998\[[@R1]\]). The cause of radiation associated BOOP syndrome is thought to be a combination of chemotherapy, endocrine therapy, and scattered radiation, but this has not been confirmed (Hamanishi et al., 2000\[[@R4]\]; Ishimatsu et al., 2000\[[@R5]\]; Kitagawa et al., 2003\[[@R8]\]; Takai et al., 2006\[[@R11]\]). Systemic corticosteroids are reported to be effective for the treatment of BOOP syndrome. However, some cases of recurrence after dose reduction or cessation of corticosteroid therapy have been reported (Miwa et al., 2004\[[@R10]\]). In the present two cases, rapid improvements were observed with systemic corticosteroid therapy, and any signs of recurrence were recognized during the observation period.

In this report, we have presented two cases of BOOP syndrome associated with postoperative radiotherapy. Recently, irradiation after breast-conserving surgery has become standard therapy for early stage breast cancer. BOOP syndrome needs to be considered as a potential complication of radiation injury to the lung, even though it occurs outside the irradiated fields.

![*Case 1:*Chest radiograph (a) and chest CT (b, c) obtained 27 weeks after irradiation, showing infiltration of the right upper and lower lung fields. Mobile infiltrative shadows were observed in the right and left lower lobes after 29 weeks of irradiation (d, e, f).](EXCLI-10-246-g-001){#F1}

![*Case 2:*Chest radiograph (a) and chest CT (b, c) obtained 26 weeks after irradiation, showing infiltration of the right upper, middle and lower lung fields. Mobile infiltrative shadows were observed in the right upper and lower lobes after 28 weeks of irradiation (d, e, f).](EXCLI-10-246-g-002){#F2}
