(Chest. 1999;115:1465-1468.)
© 1999
American College of Chest Physicians
Successful Treatment of Refractory Bronchorrhea by Inhaled Indomethacin in Two Patients With Bronchioloalveolar Carcinoma*
Sakae Homma, MD, PhD, FCCP;
Masateru Kawabata, MD;
Kazuma Kishi, MD;
Eiyasu Tsuboi, MD, PhD, FCCP;
Koji Narui, MD, PhD;
Tatsuo Nakatani, MD, PhD and
Koichiro Nakata, MD, PhD
*
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
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Abstract
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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.
Key Words: bronchioloalveolar carcinoma • bronchorrhea • indomethacin • treatment
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Introduction
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Voluminous
production of clear frothy sputum is one of the characteristic clinical
features of bronchioloalveolar carcinoma.1
2
3
Bronchorrhea, defined as the profuse production of sputum of > 100
mL/d,4
and 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.
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Case Reports
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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 x 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
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Figure 3. Microscopy of the primary lesions shows
proliferating mucus-producing bronchioloalveolar carcinoma along the
alveolar walls (hematoxylin-eosin, original magnification x50).
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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 x 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 x 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.
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Figure 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
x100).
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Discussion
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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
PGF2
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 Na2CO3.9
Aerosols
with particles with a mass median aerodynamic diameter of 1.0 to 8.0
µm 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.11
In 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.14
15
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.
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Acknowledgements
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ACKNOWLEDGMENT: The authors would like to thank Dr. Jun Tamaoki of
Tokyo Women's Medical College for illustration of the method of
inhaled indomethacin.
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Footnotes
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Abbreviations: IPF = idiopathic pulmonary
fibrosis; PG = prostaglandin; QOL = quality of life
Received for publication February 24, 1998.
Accepted for publication November 22, 1998.
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References
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Spiro, SG, Lopez-Videriero, M-T, Charman, J, et al (1975) Bronchorrhea in a case of alveolar cell carcinoma. J Clin Pathol 28,60-65[Abstract/Free Full Text]
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Tamaoki, J, Takeyama, K, Yamawaki, I, et al (1997) Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides. Am J Physiol 272,L15-L19[Abstract/Free Full Text]
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Yamaguchi, M, Eto, Y, Matsuzaki, G, et al (1995) A case in which bronchorrhea was alleviated by oral erythromycin and inhalation of beclomethasone and furosemide. Jpn J Thorac Dis (in Japanese) 33,192-196
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Abstract
Introduction
