Philippe R. Montgrain

CLASSIFICATION

The term lung cancer comprises a number of specific malignancies (Table 102-1). The four major histologic types of lung cancer are squamous cell carcinoma, adenocarcinoma, large-cell carcinoma, and small-cell carcinoma. Historically, clinicians have been concerned primarily with the division of lung cancer into small-cell lung carcinoma (SCLC) and non–small-cell lung carcinoma (NSCLC). These two major groups have very different clinical presentations, metastatic potential, and responses to therapy. However, in the past decade, there has been increased emphasis on the precise classification of NSCLC since molecular testing and potential therapies now depend on histology. For example, adenocarcinomas are more likely to harbor epidermal growth factor receptor (EGFR) mutations that respond to specific targeted inhibitors. As a result of this need for more precision, the classification of lung adenocarcinoma was further refined in 2011, as shown in Table 102-1. One major change is that the term bronchioloalveolar carcinoma (BAC) is no longer used. The four major histologic types of lung cancer are discussed below.

Squamous cell carcinoma accounts for about 20% to 25% of all lung cancers in the United States. It used to be the most common type of lung cancer, but for unclear reasons its incidence has dropped, and it is now surpassed by adenocarcinoma. Historically, the majority of squamous cell carcinomas presented as central tumors. However, more recent data suggest an increasing percentage of peripheral tumors. Cavitation is not uncommon. Morphological features include intercellular bridging, squamous pearl formation, and keratinization. Squamous cell carcinoma typically arises from altered bronchial epithelium and is preceded by years of progressive mucosal changes that include squamous metaplasia, dysplasia, and carcinoma in situ. In its early stages of growth, the tumor may appear as a small, red, granular plaque or as a focus of leukoplakia. Later, it may appear as a large exophytic endobronchial mass.

Adenocarcinoma is the most common histologic type, representing 40% to 50% of all lung cancers in the United States. Adenocarcinomas are classically peripheral tumors arising from the peripheral airways and alveoli, but they may also arise proximally from the epithelium or submucosal glands. Cavitation is rare. Morphologically, they appear as cuboidal or columnar cells forming gland-like structures that may or may not produce mucin. Some adenocarcinomas display a lepidic growth pattern, meaning growth restricted to neoplastic cells along preexisting alveolar structures without invasion. These preinvasive or minimally invasive lesions carry a better prognosis. The new 2011 classification of adenocarcinoma introduced many changes, some of which are worth highlighting. First, the term bronchioloalveolar carcinoma was discontinued and further divided into new terms (Table 102-1). Second, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma were introduced. Third, micropapillary adenocarcinoma was added as a new subtype with poor prognosis. Finally, new terminology and diagnostic criteria for small biopsies and cytology specimens were proposed. These changes will assist in determining patient therapy and predicting outcome.

SCLC comprises about 15% of all lung cancers. It has a distinct clinical presentation, with a very aggressive course and frequent metastases at presentation. Paraneoplastic syndromes are common. Though chemoresponsive, SCLC has a very poor prognosis. About two-thirds of SCLC present as a perihilar mass, though it can present as a solitary pulmonary nodule in up to 5% of cases. Extensive lymph node metastases are common, and the tumor often causes bronchial obstruction by extrinsic compression. Tumor cells are small, with a round to fusiform shape, scant cytoplasm, and absent or faint nucleoli. Nuclear molding and smearing of nuclear chromatin as a result of crush artifact can be seen. Extensive necrosis is common. Staining for neuroendocrine markers, such as CD56, chromogranin, and synaptophysin, can aid in diagnosis.

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