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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?


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.


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