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Successful Treatment of Refractory Bronchorrhea by Inhaled Indomethacin in Two Patients With Bronchioloalveolar Carcinoma* FREE TO VIEW

Sakae Homma, MD, PhD, FCCP; Masateru Kawabata, MD; Kazuma Kishi, MD; Eiyasu Tsuboi, MD, PhD, FCCP; Koji Narui, MD, PhD; Tatsuo Nakatani, MD, PhD; Koichiro Nakata, MD, PhD
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*From the Division of Respiratory Diseases, Toranomon Hospital, Tokyo, Japan.

Correspondence to: Sakae Homma, MD, PhD, FCCP, Division of Respiratory Diseases, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, 105-8470, Japan



Chest. 1999;115(5):1465-1468. doi:10.1378/chest.115.5.1465
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Bronchorrhea in patients with bronchioloalveolar carcinoma is not uncommon. However, to our knowledge, an effective treatment for bronchorrhea in these patients has not been established. Recently, we have confirmed the efficacy of inhaled indomethacin in severe refractory bronchorrhea in comparison to that of other medications in two patients with bronchioloalveolar carcinoma. Despite the administration of a macrolide and corticosteroid, sputum volume increased to 700 mL/d in case 1 and to 200 mL/d in case 2 and hypoxemia and dyspnea deteriorated. Within a few days after the initiation of treatment with inhaled nebulized indomethacin (75 mg/d), sputum volume started to decrease and was controlled to < 100 mL/d, associated with alleviation of dyspnea and hypoxemia. To our knowledge, this is the first report of successfully treated refractory bronchorrhea associated with bronchioloalveolar carcinoma by inhaled indomethacin, resulting in markedly reduced sputum volume, improved quality of life, and prolonged survival.

Abbreviations: IPF = idiopathic pulmonary fibrosis; PG = prostaglandin; QOL = quality of life

Figures in this Article

Voluminous production of clear frothy sputum is one of the characteristic clinical features of bronchioloalveolar carcinoma.13 Bronchorrhea, defined as the profuse production of sputum of > 100 mL/d,4and often the cause of exhaustion and difficulty in social life due to expectoration of large amounts of sputum, has been observed in patients with chronic bronchitis, diffuse panbronchiolitis, bronchiectasis,5 and bronchioloalveolar carcinoma. Endogenous prostaglandins (PGs) appear to play an important role in the pathophysiologic mechanisms of this excessive production of sputum, because blockade of the cyclooxygenase pathway with indomethacin decreases the production of respiratory tract fluid and mucus by inhibiting Cl secretion and glandular secretion and by enhancing sodium absorption across airway mucosa. Inhaled indomethacin for bronchorrhea has been noted as an effective treatment for reducing sputum production and improving quality of life (QOL) in a group of patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis.5 However, to our knowledge, there has been no such report of efficacy in a patient with bronchioloalveolar carcinoma. We now report the effectiveness of inhaled nebulized indomethacin for severe refractory bronchorrhea in two patients with diffusely proliferated bronchioloalveolar carcinoma resulting in markedly reduced sputum volume, improved QOL, and prolonged survival.

case 1

A 59-year-old man presented to our hospital for evaluation of cough, sputum, and left shoulder pain. He had a history of chronic pansinusitis and cigarette smoking (4 packs a day × 30 years; Brinkman index = 2,400). Since June 1994, he had had a productive cough and left shoulder pain. In September 1994, he was admitted to the hospital for these symptoms. The diagnosis was primary lung adenocarcinoma originating from the superior segment (S6) of the left lower lobe with lymphangitic carcinomatosis and left shoulder metastases (T4N2M1, stage IV) that was confirmed by sputum cytologic study and radiographic images. Chest radiograph at the time of hospital admission showed diffuse infiltrates in the left middle and lower lung fields (Fig 1). Chest CT showed air-space consolidation in the left S6 associated with diffusely scattered fine nodular densities and thickening of interlobular septa or bronchovascular bundles corresponding to lymphangitic carcinomatosis in the left lung field. Macroscopic appearance of the sputum was watery, clear, and frothy. Chest examination revealed coarse crackles in the left lower lung field.

Clinical course for the 8 months from his first visit to his death is shown in Figure 2. Arterial blood gas analysis revealed early hypoxemia without later progression. Sputum volume increased gradually from 50 to 700 mL/d during the first 4 months prior to the inhaled nebulized indomethacin therapy. Despite the initial combined administration of macrolide and corticosteroid for bronchorrhea and chemotherapy for lung cancer, sputum volume increased and hypoxemia and dyspnea deteriorated.

Over a period of 5 days after the initiation of treatment with inhaled nebulized indomethacin (75 mg/d), sputum volume started to decrease. One month later, sputum volume had decreased from 700 mL/d to < 100 mL/d in association with improvement of dyspnea and hypoxemia. Although the dose of indomethacin was increased to 150 mg/d combined with inhaled nebulized furosemide (80 mg/dL), sputum volume did not decrease to < 70 mL/d, but was controlled to < 100 mL/d.

In April 1995, the patient died of refractory respiratory failure due to diffuse dissemination of cancer cells in both lungs. Macroscopic appearance of the cut surface of the autopsied lung showed diffusely proliferating cancer cells in the air-space and thoracic cavity in the left lung and multiple small metastatic nodules in the right lung. Microscopic appearance of the primary lesion showed proliferating mucus-producing malignant cells along the alveolar walls (Fig 3). The origin of mucus production was confirmed to be these malignant cells because there was no hypertrophy of the bronchial glands and goblet cell hyperplasia of the bronchial epithelia. According to these pathologic findings, this case was diagnosed as typical mucinous (goblet cell type) bronchioloalveolar carcinoma.6

case 2

A 69-year-old man was admitted to the hospital for the first time because of dyspnea on exertion, cough, and sputum in February 1995. He had a history of chronic pansinusitis and cigarette smoking (1 pack a day × 43 years; Brinkman index = 860). Since the age of 59 years, he had had dry cough, and in 1993 he had been diagnosed as having idiopathic pulmonary fibrosis (IPF). Physical examination was notable for fine crackles in the bilateral lower lung fields and finger clubbing. Chest radiograph performed in July 1995 showed diffuse reticulonodular shadows in both the middle and lower lung fields with honeycombing in the lung bases. Chest CT showed increasing diffuse ground-glass opacities adjacent to peripheral honeycombing in both the middle and lower lung fields (Fig 4). Based on these radiographic findings and deteriorating hypoxemia, he was diagnosed as having an acute exacerbation of IPF. Despite the combined administration of large doses of corticosteroid (methylprednisolone, 1 g × 3 days) and cyclophosphamide (50 mg/d), the radiographic findings and sputum volume failed to respond. Arterial blood gas analysis revealed progressive hypoxemia without hypercapnea. Sputum volume increased gradually from 20 to 200 mL/d during the first 6 months prior to the administration of the inhaled nebulized indomethacin. Despite the administration of macrolide, corticosteroid, and inhaled furosemide (80 mg/dL) for bronchorrhea, sputum volume increased and hypoxemia and dyspnea deteriorated.

In August 1995, he was diagnosed as having primary lung adenocarcinoma associated with IPF (TXN0M1, stage IV) evidenced by sputum cytologic study. We then began the administration of inhaled nebulized indomethacin (75 mg/d) for bronchorrhea. Over the following 10 days, sputum volume decreased from 200 to 50 mL/d, associated with alleviation of dyspnea and hypoxemia. The patient was discharged from the hospital, but returned after 1 month. Although the sputum volume was controlled at < 100 mL/d, the patient died of refractory respiratory failure due to diffuse dissemination of cancer cells in both lungs in October 1995.

Macroscopic appearance of the cut surface of the autopsied lung showed diffusely solid lesions in the air-space associated with peripheral honeycombing of both lungs. Upon microscopic examination at high magnification, these solid lesions appeared to correspond to proliferating mucus-producing malignant cells along the alveolar walls without cellular interstitial pneumonia (Fig 5). The origin of mucus production was confirmed to be these malignant cells because there was no hypertrophy of the bronchial glands or goblet cell hyperplasia of the bronchial epithelia. According to these pathologic findings, this case was diagnosed as typical mucinous (goblet cell type) bronchioloalveolar carcinoma associated with IPF. Additionally, diffuse intrabronchial spreading of cancer cells in both lungs was suggested, because there were no hematogenous remote metastases.

The mechanisms pertaining to excessive production of sputum may be divided into three categories: (1) hypersecretion of mucus glycoprotein and other glandular products from mucus glycoprotein-producing cells; (2) increased transepithelial Cl secretion; and/or (3) excessive transudation of plasma products into the airway space.7 Regarding the second category, both PGE2 and PGF stimulate Cl secretion toward the lumen and, hence, promote water accumulation.8 Thus, the decrease in sputum production by indomethacin may be associated with the impaired synthesis of PGs in the airway because the content of cyclooxygenase products in the sputum was remarkably reduced in the indomethacin group as compared with the placebo group.5 Therefore, this second mechanism appears to play a major role in the effectiveness of indomethacin therapy for bronchorrhea.

In this report, patients received 2 mL of an aerosol preparation that contained 25 mg of indomethacin (Banyu Pharmaceutical; Tokyo, Japan) dissolved in sterile saline solution in which the pH had been adjusted to 7.40 with Na2CO3.9Aerosols with particles with a mass median aerodynamic diameter of 1.0 to 8.0μ m were delivered from a nebulizer (Millicon Nebulizer; Shin-Ei Industry Co Ltd; Saitama, Japan) and these inhalations were administered three to six times daily. While our trial of inhaled nebulized indomethacin in two patients with bronchioloalveolar carcinoma elicited a decrease in the daily production of bronchorrhea sputum and improved breathlessness and dyspnea without side effects, another trial of a 4-week treatment with oral indomethacin for bronchorrhea in patients with bronchiectasis showed no benefit with regard to lung inflammation and sputum volume.10 Therefore, there might be different mechanisms on the effect of indomethacin for bronchorrhea according to the route of administration.

Previous to this report, only one case of bronchioloalveolar carcinoma treated by inhaled indomethacin had been reported. In that case report, the patient died 4 months after the initial symptoms of bronchorrhea did not respond and sputum volume did not decrease after inhaled indomethacin therapy, although respiratory difficulties improved due to the increased viscosity of sputum that resulted in an easier expectoration.11In our two cases, the survival times from first visit to death were 8 months in case 1 and 9 months in case 2. These results showed that the inhalation therapy contributed not only to an improved QOL but also to prolonged survival, since the median survival time was 4.5 months for stage IV bronchioloalveolar carcinoma in a previous report.12

Regarding mucus hypersecretion, lipopolysaccharide causes neutrophil accumulation in the airway mucosa and a corresponding stimulation of goblet cell secretion, and pretreatment with 14-membered macrolide antibiotics such as clarithromycin and erythromycin specifically inhibit these inflammatory reactions. These findings may explain the clinical benefit of macrolides in the treatment of neutrophil-associated airway hypersecretion.13 Furthermore, corticosteroids or furosemide have been reported to have an inhibitory effect on mucus secretion in bronchorrhea.1415 In other reported cases with bronchorrhea associated with bronchioloalveolar carcinoma that were treated with atropine, corticosteroids, infiltration of the stellate ganglion, radiotherapy, and antihistamine, no reduction in sputum volume was obtained.2 In our two cases, erythromycin and corticosteroids or inhaled furosemide had been tried before the initiation of inhaled indomethacin, but no reduction in sputum volume was noted. Additionally, histopathologic findings of the autopsied lungs in our two cases revealed neither neutrophil accumulation and goblet cell hyperplasia in the airway mucosa nor bronchial glandular hypertrophy. These results suggest that the mechanism of bronchorrhea in patients with bronchioloalveolar carcinoma is mainly through increased transepithelial Cl secretion and not neutrophil-associated airway hypersecretion or glandular hypersecretion.

The incidence of lung cancer is as high as 48% in patients with IPF, and 10% in patients without IPF in our hospital.16 In fact, we commonly suspect the association of bronchioloalveolar carcinoma when we see a patient with the complaint of excessive production of sputum during the course of IPF because it is an unusual clinical manifestation in IPF. Thus, attention should be paid to sputum volume in patients with IPF to avoid overlooking its association with the malignant process.

In conclusion, we described the efficacy of inhaled indomethacin in severe refractory bronchorrhea in two patients with bronchioloalveolar carcinoma. To our knowledge, this is the first report of the effectiveness of inhaled indomethacin on voluminous bronchorrhea associated with diffusely proliferated bronchioloalveolar carcinoma. The treatment resulted in marked reduction of sputum volume, improvement of QOL, and prolonged survival. This may be a new therapeutic modality for such patients with end-stage disease, and it is essential to institute this treatment early in the course of the illness.

Figure Jump LinkFigure 1. Chest radiograph on hospital admission, showing diffuse infiltrative shadow in the left middle and lower lung fields (posteroanterior view).Grahic Jump Location
Figure Jump LinkFigure 3. Microscopy of the primary lesions shows proliferating mucus-producing bronchioloalveolar carcinoma along the alveolar walls (hematoxylin-eosin, original magnification ×50).Grahic Jump Location
Figure Jump LinkFigure 4. Chest CT in July, showing increased diffuse ground-glass opacities adjacent to peripheral honeycombing in both the middle and lower lung fields.Grahic Jump Location
Figure Jump LinkFigure 5. Microscopy with high magnification shows that the solid lesions corresponded to proliferating mucus-producing bronchioloalveolar carcinoma along the alveolar walls without cellular interstitial pneumonia (hematoxylin-eosin, original magnification× 100).Grahic Jump Location

ACKNOWLEDGMENT: The authors would like to thank Dr. Jun Tamaoki of Tokyo Women’s Medical College for illustration of the method of inhaled indomethacin.

Homma, H, Kira, S, Takahashi, Y, et al (1975) A case of alveolar cell carcinoma accompanied by fluid and electrolyte depletion through production of voluminous amounts of lung liquid.Am Rev Respir Dis111,857-862. [PubMed]
 
Spiro, SG, Lopez-Videriero, M-T, Charman, J, et al Bronchorrhea in a case of alveolar cell carcinoma.J Clin Pathol1975;28,60-65. [PubMed] [CrossRef]
 
Hidaka, N, Nagao, K Bronchioloalveolar carcinoma accompanied by severe bronchorrhea.Chest1996;110,281-282. [PubMed]
 
Keal, EE Biochemistry and rheology of sputum in asthma.Postgrad Med J1971;47,171-177. [PubMed]
 
Tamaoki, J, Chiyotani, A, Kobayashi, K, et al Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis.Am Rev Respir Dis1992;145,548-552. [PubMed]
 
Clayton, F The spectrum and significance of bronchioloalveolar carcinomas.Pathol Annu1988;23,361-394. [PubMed]
 
Lundgren, JD, Shelhamer, JH Pathogenesis of airway mucus hypersecretion.J Allergy Clin Immunol1990;85,399-417. [PubMed]
 
Al-Bazzaz, F, Yadava, VP, Westenfelder, C Modification of Na and CL transport in canine tracheal mucosa by prostaglandins.Am J Physiol1981;240,F101-F105. [PubMed]
 
Chiba, K, Takahashi, M, Hayase, N, et al Preparation and stability of indomethacin solution.Iyaku (in Japanese)1990;26,1173-1178
 
Llewellyn-Jones, CG, Johnson, MM, Mitchell, JL, et al In vivostudy of indomethacin in bronchiectasis: effect on neutrophil function and lung secretion.Eur Respir J1995;8,1479-1487. [PubMed]
 
Kawaguchi, S, Kobayashi, H, Kanou, S, et al Effect of inhaled indomethacin for bronchorrhea in a case of bronchioloalveolar carcinoma.Lung Cancer (in Japanese)1994;34,531-535
 
Hsu, CP, Chen, CY, Hsu, NY Bronchioloalveolar carcinoma.J Thorac Cardiovasc Surg1995;110,374-381. [PubMed]
 
Tamaoki, J, Takeyama, K, Yamawaki, I, et al Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides.Am J Physiol1997;272,L15-L19. [PubMed]
 
Yamaguchi, M, Eto, Y, Matsuzaki, G, et al A case in which bronchorrhea was alleviated by oral erythromycin and inhalation of beclomethasone and furosemide.Jpn J Thorac Dis (in Japanese)1995;33,192-196
 
Marom, Z, Shelhamer, J, Alling, D, et al The effects of corticosteroids on mucous glycoprotein secretion from human airways in vitro.Am Rev Respir Dis1984;129,62-65. [PubMed]
 
Matsushita, H, Tanaka, S Lung cancer associated with usual interstitial pneumonia.Mol Med (in Japanese)1995;32,1150-1156
 

Figures

Figure Jump LinkFigure 1. Chest radiograph on hospital admission, showing diffuse infiltrative shadow in the left middle and lower lung fields (posteroanterior view).Grahic Jump Location
Figure Jump LinkFigure 3. Microscopy of the primary lesions shows proliferating mucus-producing bronchioloalveolar carcinoma along the alveolar walls (hematoxylin-eosin, original magnification ×50).Grahic Jump Location
Figure Jump LinkFigure 4. Chest CT in July, showing increased diffuse ground-glass opacities adjacent to peripheral honeycombing in both the middle and lower lung fields.Grahic Jump Location
Figure Jump LinkFigure 5. Microscopy with high magnification shows that the solid lesions corresponded to proliferating mucus-producing bronchioloalveolar carcinoma along the alveolar walls without cellular interstitial pneumonia (hematoxylin-eosin, original magnification× 100).Grahic Jump Location

Tables

References

Homma, H, Kira, S, Takahashi, Y, et al (1975) A case of alveolar cell carcinoma accompanied by fluid and electrolyte depletion through production of voluminous amounts of lung liquid.Am Rev Respir Dis111,857-862. [PubMed]
 
Spiro, SG, Lopez-Videriero, M-T, Charman, J, et al Bronchorrhea in a case of alveolar cell carcinoma.J Clin Pathol1975;28,60-65. [PubMed] [CrossRef]
 
Hidaka, N, Nagao, K Bronchioloalveolar carcinoma accompanied by severe bronchorrhea.Chest1996;110,281-282. [PubMed]
 
Keal, EE Biochemistry and rheology of sputum in asthma.Postgrad Med J1971;47,171-177. [PubMed]
 
Tamaoki, J, Chiyotani, A, Kobayashi, K, et al Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis.Am Rev Respir Dis1992;145,548-552. [PubMed]
 
Clayton, F The spectrum and significance of bronchioloalveolar carcinomas.Pathol Annu1988;23,361-394. [PubMed]
 
Lundgren, JD, Shelhamer, JH Pathogenesis of airway mucus hypersecretion.J Allergy Clin Immunol1990;85,399-417. [PubMed]
 
Al-Bazzaz, F, Yadava, VP, Westenfelder, C Modification of Na and CL transport in canine tracheal mucosa by prostaglandins.Am J Physiol1981;240,F101-F105. [PubMed]
 
Chiba, K, Takahashi, M, Hayase, N, et al Preparation and stability of indomethacin solution.Iyaku (in Japanese)1990;26,1173-1178
 
Llewellyn-Jones, CG, Johnson, MM, Mitchell, JL, et al In vivostudy of indomethacin in bronchiectasis: effect on neutrophil function and lung secretion.Eur Respir J1995;8,1479-1487. [PubMed]
 
Kawaguchi, S, Kobayashi, H, Kanou, S, et al Effect of inhaled indomethacin for bronchorrhea in a case of bronchioloalveolar carcinoma.Lung Cancer (in Japanese)1994;34,531-535
 
Hsu, CP, Chen, CY, Hsu, NY Bronchioloalveolar carcinoma.J Thorac Cardiovasc Surg1995;110,374-381. [PubMed]
 
Tamaoki, J, Takeyama, K, Yamawaki, I, et al Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides.Am J Physiol1997;272,L15-L19. [PubMed]
 
Yamaguchi, M, Eto, Y, Matsuzaki, G, et al A case in which bronchorrhea was alleviated by oral erythromycin and inhalation of beclomethasone and furosemide.Jpn J Thorac Dis (in Japanese)1995;33,192-196
 
Marom, Z, Shelhamer, J, Alling, D, et al The effects of corticosteroids on mucous glycoprotein secretion from human airways in vitro.Am Rev Respir Dis1984;129,62-65. [PubMed]
 
Matsushita, H, Tanaka, S Lung cancer associated with usual interstitial pneumonia.Mol Med (in Japanese)1995;32,1150-1156
 
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