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A 33-year-old woman was
evaluated because of persistent pulmonary infiltrates. She
was well until 7 months ago, when she developed fever, a
productive cough, and left-sided pleuritic chest pain. A
chest radiograph showed an infiltrate in the left lower
lobe. Several courses of antibiotics led to an improvement
of her symptoms, though a dry cough persisted. Subsequent
chest CT showed attenuating airspace disease in the left
lower lobe with air bronchograms and ill-defined nodules in
both lungs. Before her current presentation, she underwent
2 bronchoscopic procedures, with transbronchial biopsy
performed during the most recent one. All bacterial
cultures were negative, and cytology and pathology failed
to reveal malignancy. Given the lack of an infectious
etiology, corticosteroids were started. However, the
patient's condition did not improve.
On evaluation in the emergency department, the patient was
asymptomatic except for a persistent cough with clear
sputum. She was a nonsmoker and had no previous pulmonary
disease. She did not have a history of tuberculosis or
known exposure to risk factors. A purified protein
derivative of tuberculin (PPD) test performed 3 months ago
yielded negative results. She has not been taking any drugs
and has no known allergies. Physical examination revealed a
well-appearing woman in no distress with a respiratory rate
of 16 breaths per minute, a temperature of 35.9°C, a blood
pressure of 110/60 mm Hg, and a heart rate of 95 beats per
minute. Her lungs were clear, with no wheezing, rhonchi, or
rales. Her heart sounds were normal, with no murmurs. The
remainder of her examination yielded unremarkable findings.
Chest CT was performed (see Image). Positron emission
tomography (PET) showed increased uptake in the left
posterior portion of the lower lung with a standard uptake
value (SUV) of 6.5 and no uptake in the nodules or hilar or
mediastinal nodes.
What is the diagnosis?
Answer
Bronchoalveolar
carcinoma (BAC): Biopsies of the left lower and
upper lobes of the lung were performed by means of
video-assisted thoracoscopic surgery (VATS). The
results indicated a stage IV BAC.
Despite serial chemotherapy over 4 years, the
disease progressed (see Image 2). The pulmonary
infiltrates expanded and became cavitated. The
patient's respiratory status worsened, and she
became oxygen dependent at rest. Recurrent pulmonary
infections and airway obstruction secondary to tumor
progression resulted in progressive respiratory
failure, which ultimately led to her death.
Lung cancer is the most common cancer worldwide and
has the greatest mortality rate. Lung adenocarcinoma
is the most common histologic form of lung cancer
(31.5%). Its frequency is rising in women and in
nonsmokers. BAC is a subtype of lung adenocarcinoma
and has a wide variety of distinct clinical
manifestations, which often lead to an initial
misdiagnosis. It is relatively rare (accounting for
2.6% of all the lung cancers), and it is seen mainly
in women aged 40-70 years. It typically has a
relatively indolent course, and its association with
smoking is weaker than that of other forms of lung
cancer.
In 1999, the World Health Organization
(WHO)–International Association for the Study of
Lung Cancer (IASLC) classification defined BAC as an
adenocarcinoma with a lepidic growth pattern (growth
along intact alveolar septa) without invasive
growth, such that the alveolar architecture remains
intact. Patients with BAC may present with one or
several nodules or with diffuse parenchymal
infiltrates. More than 50% of BACs may be associated
with focal scars. A final diagnosis of BAC can be
achieved only by analyzing a surgical specimen.
Metastatic adenocarcinomas can mimic BACs;
therefore, a history of an extrathoracic
adenocarcinoma precludes the diagnosis of BAC.
The 2 main histologic types of BAC are mucinous and
nonmucinous. The mucinous type (41-60%) has a
colloid-like histologic appearance because of mucin
that fills the adjacent alveoli. In clinical terms,
this finding manifests as the expectoration of
mucoid material. The mucinous form tends to be
multicentric and often causes lobar consolidation
resembling that of pneumonia, and it worsens the
patient's prognosis. Whether the multicentricity is
due to aerogenous or lymphatic spread or the
expression of several independent malignant clones
is still debated.
The nonmucinous type (21-45%) is composed of
cuboidal or columnar cells. It is most likely to
result in a solitary nodule and improves the
prognosis. Approximately 12-14% of BACs are of a
mixed subtype, and as many as 7% are indeterminate.
About 50-60% of patients are asymptomatic in the
early stages, and the diagnosis may be made
incidentally during chest radiography. Cough (35%),
sputum (24%), and shortness of breath (15%) are
usually seen in only advanced disease. Weight loss,
hemoptysis, and fever occur less frequently than
these other findings. Bronchorrhea (5%) is a late
sign and most often associated with the diffuse,
mucinous form. Diffuse filling of the alveolar
spaces by mucin causes severe hypoxia, which is also
a manifestation of late disease.
The radiologic presentation of BAC varies, ranging
from solitary (43%) or multiple (27%) nodules to
diffuse airspace disease (30%). The CT attenuation
of these forms ranges from that of soft tissue
(frank infiltrate) to ground-glass opacity (hazy
shadow). A solitary pulmonary nodule is typically
peripheral, slowly growing, and unlikely to evolve
to widespread disease. Airspace disease (pneumonic
form) can be indistinguishable from pneumonia and is
due to a combination of tumor cells and mucin.
Multiple nodules are often bilateral and sometimes
mimic pulmonary metastatic disease. In rare cases,
BAC can manifest as lobar atelectasis or as cysts
and cavities (7%).
Certain radiologic signs should raise a clinician's
suspicion for BAC: air bronchograms (open bronchus
in an area of infiltrate), pseudocavitation
(low-attenuation regions in a nodule), or a CT
angiographic sign (visualization of vessels in
regions of consolidation after intravenous
administration of contrast material).
PET is often used to evaluate BAC. BAC usually has
an SUV lower than that of other lung cancer
subtypes; the decreased value is due to low
metabolic activity or low cellularity. In general,
negative PET results are associated with focal
disease, and increased uptake is associated with
diffuse and poorly differentiated forms.
The differential diagnosis of the pneumonic form of
BAC includes all the infectious causes of
nonresolving pneumonia, other primary or metastatic
lung malignancies, lymphoma, sarcoidosis, pulmonary
alveolar proteinosis, diffuse alveolar hemorrhage,
vasculitis, eosinophilic pneumonia, bronchiolitis
obliterans organizing pneumonia (BOOP), or pulmonary
edema.
The mucinous type, diffuse lesions, and symptomatic
disease, are associated with a worsened prognosis.
Patients with disease in the T1N0M0 stage have a
90.5% 5-year survival rate, as opposed to those with
diffuse bilateral disease, who have 0% survival at 5
years. A 100% 5-year survival rate is reported for
BAC with a >75% lepidic growth pattern and a
central scar <5 mm or an intact elastic-fiber
framework.
No optimal therapy has been defined for recurrent or
advanced BAC. The response rate to conventional
chemotherapy is low (14% response rate to a 96-h
infusion of paclitaxel). Recent studies showed
improved results with epidermal growth factor (EGFR)
or tyrosine kinase inhibitor. Women without a
history of smoking appear to respond most often to
gefitinib. The reported response rate is 12-19% for
gefitinib and 26% for erlotinib. Somatic mutations
of EGFR appear to make the BAC responsive to these
targeted inhibitors in approximately only 10% of
patients. Surgical options include curative
resection for limited forms (usually up to 3
separate nodules), palliative resection, or,
potentially, lung transplantation.
This case involved a rare presentation of the
pneumonic form of BAC in a young patient with a poor
response to treatment. BAC has clinical, histologic,
and radiographic characteristics distinct from those
of other non–small cell lung cancers. Being
familiar with the multiple forms of presentation of
BAC can help in the early diagnosis and subsequent
treatment of a potentially curable disease.
References
- Daly RC, Trastek VF, Pairolero PC, et al.
Bronchoalveolar carcinoma: factors affecting
survival. Ann Thorac Surg 1991
Mar;51(3):368-376.
- Lee KS, Kim Y, Han J, et al.
Bronchioloalveolar carcinoma: clinical,
histopathologic and radiologic findings. Radiographics
1997;6:1345-1357.
- Lynch TJ, Bell DW, Sordella R, et al.
Activating mutations in the EGFR underlying
responsiveness of NSCLC to Gefitinib. N Engl
J Med 2004;350:2129-2139.
- Perez-Soler R. The role of erlotinib (Tarceva,
OSI 774) in the treatment of non-small cell lung
cancer. Clin Cancer Res
2004;10:4238s-4240s.
- Sabloff BS, Wistuba II, Erasmus JJ. Cystic
bronchioloalveolar cell carcinoma. J Thorac
Imaging 2005;20(2):110-114.
- Travis WD. Pathology of lung cancer. Clin
Chest Med 2002;23(1):65-81.
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