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; https://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.
