In this issue of Oncology, Levy and colleagues provide a comprehensive review of bronchioloalveolar carcinoma [BAC], with a focus on the management of this rare disease, which represents 4% of all lung cancers. The definition of BAC was revised by the World Health Organization (WHO) in 2004, with changes made to the diagnostic criteria and classification. BAC was defined as an adenocarcinoma of the lung that grows in a lepidic fashion along the alveolar septa without invasion of stroma, blood vessels, or pleura. BAC has been sub-classified into three types: nonmucinous, mucinous, and mixed.
Because of the rarity of BAC and the recent change in its definition, risk factors associated with the development of BAC are poorly understood. Smoking has not always been thought to be a risk factor for BAC.[3, 4] It is estimated that approximately 30% of patients with BAC are never-smokers, compared with 15% of patients with adenocarcinoma and 5% of patients with squamous cell carcinoma. However, case control studies have demonstrated an association between BAC and intensity of cigarette smoking. There is also the paradox that nonmucinous BAC, which is more prone to EGFR mutation, is more significantly associated with smoking habits than mucinous BAC, which is more prone to K-ras mutation.
Jaagsiekte Sheep Retrovirus (JSRV) is a ß-retrovirus that is highly infectious in sheep and that induces low-grade tumors resembling BAC. This observation led to the hypothesis that the same virus could be linked with human BAC. However, molecular studies in human BAC have not been able to confirm this hypothesis, and at this time no convincing evidence exists of such a link.
Pulmonary congenital cystic airway malformations are thought to be the only precursor lesions for mucinous BAC; these usually occur in young adults.[7, 8] Type 1 congenital cystic adenomatoid malformation is the most common malformation of the lung and is often localized in the lower lobes; this is the only type of airway malformation that presents as intracystic mucinous cell clusters that resemble mucinous BAC and that have the same differentiation profile. Moreover, the high frequency of K-ras mutations and loss of heterozygosity and/or microsatellite alterations at the p16 locus in these lesions justifies their consideration as mucinous BAC precursors. Scarring from other pulmonary diseases and occupational exposures may also be responsible for BAC.
BAC is generally not very symptomatic and is associated with a slow rate of growth and progression and a good prognosis. BAC features in mixed adenocarcinoma are also consistently associated with a good prognosis. A recent study showed that the new TNM staging system may more accurately reflect the prognosis of BAC than the previous system.
The more common nonmucinous BAC evolves from terminal respiratory unit cells (type II pneumocytes and Clara cells). This form of BAC presents more often as a ground-glass opacity on radiographs, with approximately 45% of patients demonstrating EGFR mutations—and an even higher percentage doing so in Asian populations. The prognosis of nonmucinous BAC is better than that of the less common mucinous BAC, which is derived from metaplasia of bronchiolar epithelia and which presents more frequently as a pneumonic-type infiltrate, with frequent K-ras mutations (in approximately 30% of cases). Recently, mucinous BAC was reported in a 22-year-old man with Peutz-Jeghers syndrome. This autosomal dominant inherited disorder is related to a STK11/LKB1 germline mutation. Molecular studies of the patient’s BAC revealed loss of heterozygosity in the region of STK11. Inactivating somatic mutations of STK11 have been described in primary human lung adenocarcinomas and in a smaller percentage of squamous cell carcinomas. Although EGFR and STK11 mutations are usually mutually exclusive, STK11 mutations can occur concurrently with K-ras mutations. These observations raise the question of the potential role of STK11 in the pathogenesis of mucinous BAC.
Whether multifocal BAC is clonal in origin is a question to which there is currently no definitive answer. The multifocality of lung nodules may be caused by either the dissemination of malignant cells from the primary tumor or the synchronous development of multifocal independent lesions. Distinguishing between these two possibilities has important therapeutic and prognostic implications. Two recent studies have investigated the clonality of multifocal BAC by studying synchronous or metachronous lesions. In the first study, the authors examined 56 pulmonary nodules presenting as ground-glass opacity in 24 patients. In 75% of patients, the multiple lesions had a heterogeneous genetic status (ie, a combination of both EGFR and K-ras mutations); these findings favor a hypothesis of multifocal independent lesions. In the second study, which is based on an analysis of 17 cases of sequential BAC-related adenocarcinomas in patients who had not been treated with EGFR tyrosine kinase inhibitors, the authors propose 3 different hypotheses:  no significant EGFR evolution for a single clone (ie, the same mutation found in sequential tumor samples), which indicates subsequent disease progression;  genetic alterations from mutant to wild-type EGFR, which suggest multifocal lesions [ie, new primary carcinomas]; or  a switch from wild-type to mutant EGFR, a scenario that does not allow any conclusion. We agree with the authors’ conclusion that when additional lesions emerge after the radical resection of BAC-related cancer, sequential tumor samples should be obtained to help define subsequent treatment strategy.
Molecular profiling studies focusing on BAC are scarce. Three seminal studies using high-density oligonucleotide arrays to study lung adenocarcinoma transcriptome were published in the early 2000s.[18-20] These studies showed that adenocarcinomas were heterogeneous, capable of being classified into three or four subcategories; one or two of these subcategories were enriched in BAC (ie, adenocarcinomas with BAC features) and were associated with an improved prognosis. However, these studies were published before 2004. The authors of a meta-analysis of these three studies (which was published in 2006) state that the histology had not been centrally reviewed and that it was therefore not possible to distinguish pure BAC from adenocarcinoma with BAC features. More recent studies using the 2004 classification have confirmed that pure BAC and mixed adenocarcinomas were enriched in one of the clusters; however those studies included only a handful of cases of pure BAC.[22, 23] Only one study evaluated carefully the genomic differences between nonmucinous BAC and mixed-type adenocarcinoma with BAC features, as delineated by the WHO 2004 definition. The authors identified 113 genes that best differentiated nonmucinous BAC from adenocarcinoma with BAC features, and correlative gene expression analysis demonstrated that a high percentage of these were markers of a poor prognosis in early stage adenocarcinoma—ie, PDCD6 and TERT. A careful clinical, radiological, and pathological description of the samples included in such high-throughput profiling studies is key to progress in our understanding of lung adenocarcinomas and BAC.
Since 1984, the year of the first description of K-ras mutations in lung cancer, and 2004, the year of the discovery of EGFR-activating mutations, much progress has been made in identifying key oncogenic drivers in both smokers and never-smokers with lung adenocarcinomas (EGFR, HER2, MEK1, BRAF, ALK-EML4 fusion, PI3KCA, PDGFR amplification, ROS fusion, K-ras in smokers; and EGFR, K-ras, HER2, ALK-EML4 fusion in never-smokers).[26-28]. High-throughput mutational analysis as well as the rapid development of deep sequencing of cell lines and human tumors will be instrumental in filling the knowledge gap with respect to tumors with unknown oncogenic drivers, although the results of such studies will likely affect a small fraction of patients. Data suggest that carcinomas may contain multiple, partially redundant mutations, perhaps in distinct clonal populations, rather than being addicted to a single oncogene. The identification of recurrent driver mutations in small populations will require the sequencing of many samples. A recent example is the identification of NKX2-1 on 14q13.3, which was found to be amplified and to be a new candidate proto-oncogene in approximately 12% of 528 lung adenocarcinomas analyzed with single-nucleotide polymorphism arrays. Collaborative efforts to include homogeneous cohorts of rare but well-defined clinical and pathological entities, such as mucinous BAC or nonmucinous BAC [ideally prospectively collected in clinical trials], in large scale sequencing studies may help in the interpretation of the exponential amount of data that is being generated. Integrative analyses using data generated by various technologies to profile different elements of the cell [genome, transcriptome, proteome] will also be crucial in this regard. Ultimately, each tumor is probably unique, even within a given type and subtype. Understanding the set of changes at the individual patient level will hopefully facilitate the practice of personalized medicine.
Financial Disclosure: The authors have no significant financial interest or other relationships with the manufacturers of any products or providers of any service mentioned in this article.