Atypical adenomatous hyperplasia is classiﬁed by the World Health Organization (WHO) as a putative precursor of adenocarcinoma (ACA), especially bronchioloalveolar carcinoma (BAC). ACA is deﬁned as a malignant epithelial tumor with glandular differentiation or mucin production. ACA is the most common cell type in the United States and many developed countries. It accounts for 37% of all lung cancers in the Surveillance, Epidemiology and End Results (SEER) database (40% in women; 33% in men; http://seer. cancer.gov). ACA histology is associated with cigarette smoking, but the association is not as strong as it is for squamous cell and small cell carcinoma. ACA is the most common histology of lung cancer in never smokers, especially women.
Bronchioloalveolar cell, also called alveolar cell, is classiﬁed by the WHO as a subtype of ACA. BACs are mostly moderate or well-differentiated tumors and grow along preexisting alveolar structures (lepidic growth) without evidence of invasion. If there is evidence of invasion, then the tumor is classiﬁed as ACA mixed type. Pure BAC by the current classiﬁcation is a rare tumor; most are ACA mixed type. It is anticipated that pure BAC will be renamed as adenocarcinoma in situ in the new classiﬁcation.
ACAs are usually peripherally located in the lungs. Because of the peripheral location, more of the patients are asymptomatic, and the lesion is detected on an incidental chest radiograph. Patients may present with a new cough, chest pain, or less commonly hemoptysis. Presenting symptoms caused by distant metastases to the bone, brain, or liver are common with all cell types, especially ACA and large cell carcinoma. Individuals with BAC may present with an asymptomatic solitary pulmonary nodule, pneumonia such as consolidation of the lung, or rarely with a profound bronchorrhea. Bronchorrhea is usually seen in those with extensive bilateral lung involvement.
The most common radiographic presentation is a peripheral lung nodule or mass (mass deﬁned as 3 cm) in maximum diameter. It may infrequently present as a central mass and rarely cavitates. ACA is the most common cell type to present with a malignant pleural effusion.
Sputum cytology results are rarely positive. Diagnostic yields with bronchoscopy are less than with squamous cell or small cell carcinoma because of the peripheral location. For lesions that are 2 cm in diameter or larger, the diagnostic yields are approximately 60% to 70%. Transthoracic needle aspirations (TTNAs) are diagnostic in 85% to 90% of all lesions and are the preferred diagnostic test for lesions smaller than 2 cm in diameter. The beneﬁts of TTNA should be balanced against the risk of pneumothorax, especially in patients with chronic obstructive pulmonary disease or emphysema. Thoracentesis and pleural ﬂuid cytology is the preferred diagnostic test in individuals with pleural effusion.
The treatment of choice for patients with stage I, II, or IIIA/B is generally the same as for all non–small cell lung cancers. Patients with stage IV (metastatic) disease have generally been treated with systemic chemotherapy as palliative treatment. In recent years, a number of genetic alterations have been identiﬁed in the tumor that are changing the treatment approach. Some ACAs have been identiﬁed to have a mutation in the intracellular domain of the epidermal growth factor receptor (EGFR) gene. The predominant mutations include in frame deletions of exon 19 and missense mutation in exon 21. These mutations have been associated with a high response rate to treatment with the EGFR tyro- sine kinase inhibitors (TKIs) geﬁtinib and erlotinib. For reasons that are currently unknown, the frequency of the EGFR tyrosine kinase mutations vary in different ethnic populations. The frequency of mutation in North America and Europe is approximately 15% of all ACA versus 30% of ACA in East Asians. These mutations are almost exclusively limited to the ACA cell type.
Recent reports have documented better survival in individuals when these EGFR mutations are treated initially with EGFR TKIs versus conventional chemotherapy. Other studies have shown that KRAS mutations, which occur in 20% to 30% of patients with ACA, confer resistance to treatment with the EGFR inhibitors. Mutations in KRAS and EGFR are almost always mutually exclusive. It is very likely that future identiﬁcation of genetic mutations or identiﬁcation of predominant intracellular pathways of malignant cells will inﬂuence the choice of treatment of ACA and other histologies. Most recently a mutation of anaplastic lymphoma kinase (ALK) has been identiﬁed in 3% to 5% of ACA, and promising new treatment with the tyrosine kinase inhibitor crizotinib has been reported.