Excluding non-melanoma skin cancers (squamous cell carcinoma of the skin and basal cell carcinoma of the skin), bronchogenic carcinoma represents the second most common cancer in the United States (see Fig. 32.1) and the most common cause of cancer-related death in men and women. The development of bronchogenic carcinoma is a multistep process in which numerous specific mutations accumulate in a temporal sequence. Common oncogenes involved in the pathogenesis of bronchogenic carcinomata include c-MYC, k-RAS, EGFR, c-MET, and c-KIT. Tumor suppressor genes that are commonly deleted or inactivated in the pathogenesis of bronchogenic carcinoma include p53, RB, p16, and unknown genes on the short arm of chromosome 3. Risk factors for the development of bronchogenic carcinoma are discussed in Chap. 32 and include tobacco smoking. Of note, tobacco smoking also increases the risk of the development of cancer of the lip, tongue, floor of the mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, and kidney.
Bronchogenic carcinoma is further subclassified by microscopic morphologic criteria. Broadly speaking, there are four major types of bronchogenic carcinoma, and each can be further subtyped. All types are associated with cigarette smoking and are aggressive, locally invasive, and frequently are already widely metastatic at the time of diagnosis. Furthermore, all types are associated with paraneoplastic syndromes (Chap. 32). The four major types of bronchogenic carcinoma are squamous cell carcinoma (SCCA), adenocarcinoma, large cell carcinoma, and small cell carcinoma (Fig. 31.2).
Relative frequencies of bronchogenic carcinoma in men (left) and women (right), by morphologic pattern. Data by Wahbah et al. Ann Diagn Pathol. 2007;11:89.
Squamous cell carcinoma is more common in men and generally is a central disease (Fig. 31.3), often with central necrosis, cavitation, and hilar lymph node involvement. However, the incidence of SCCA in more peripheral lung locations is increasing. Microscopically, SCCA is characterized by production of keratin and/or by the presence of intercellular bridges between malignant epithelial cells. In well-differentiated SCCAs, keratin and/or intercellular bridges may be easily identified; in more poorly differentiated SCCA, mitotic activity is typically increased, and keratin and intercellular bridges are more difficult to identify. Variants of SCCA include papillary, clear cell, small cell (not to be confused with small cell carcinoma, see below), and basaloid. Common genes implicated in the pathogenesis of SCCA include p53, RB, p16, and many others.
Squamous cell carcinoma (SCCA) is typically located near the hilum, as in this example (a). (b) Histologically, the malignant cells of SCCA have intercellular bridges between cells (not identifiable at this magnification). In this well-differentiated SCCA, keratin production is present; the arrow indicates a keratin pearl, which is seen at higher magnification in (c). (a): From Kemp et al. Pathology: the Big Picture, McGraw-Hill; 2008.
Adenocarcinoma is more common in women and generally is a peripheral lung disease (Fig. 31.4). It is the most common primary lung cancer in nonsmokers, and the most common type of bronchogenic carcinoma in men and women (previously, SCCA was most common in men). Microscopically, adenocarcinoma shows mucin production and/or gland formation, features that are more easily recognized in well differentiated tumors than in poorly differentiated tumors. Variants of adenocarcinoma include acinar, papillary, bronchioloalveolar, and solid. Of the subtypes, bronchioloalveolar carcinoma stands out as distinct not only grossly and microscopically but also clinically and is further discussed below. Common genes implicated in the development of adenocarcinoma include k-RAS, p53, RB, p16, EGFR, and c-MET.
Adenocarcinoma is typically located in the lung periphery, far removed from the hilum, as in the example (a). (b) This example of adenocarcinoma shows a well-differentiated neoplasm, with easily recognizable glands. In the setting of a more poorly differentiated neoplasm, special stains and/or immunohistochemical analysis may be necessary to demonstrate glandular differentiation. (a): From Kemp et al. Pathology: the Big Picture, McGraw-Hill; 2008.
Bronchioloalveolar adenocarcinoma is typically a peripheral, multinodular lesion that grows along the preexisting framework of acini without destruction of its architecture. This growth pattern is called lepidic, a somewhat colorful term likening the growth of neoplastic cells to butterflies sitting atop a fence (Fig. 31.5). The bronchioloalveolar subtype of adenocarcinoma, in contrast to other adenocarcinoma subtypes, shows no significant association with smoking. Bronchioloalveolar carcinoma is further subclassified into mucinous and nonmucinous subtypes, with the latter more likely to show aerogenous spread and, hence, be multinodular (Fig. 31.6).
Bronchioloalveolar carcinoma is a subtype of adenocarcinoma characterized by growth of malignant cells along alveolar septa. Bronchioloalveolar carcinoma is further subdivided into nonmucinous (a) and mucinous (b) subtypes.
Bronchioloalveolar carcinoma is frequently multinodular, especially if it is nonmucinous. Note the numerous nodules spread throughout the cut surface of the lung. Courtesy of Dr. R.A. Cooke, Brisbane, Australia.
Large cell carcinoma is an anaplastic carcinoma in which the large malignant cells are so poorly differentiated as to defy further classification. Since many show minimal squamous or glandular differentiation at the ultrastructural level, most large cell carcinomata likely represent very poorly differentiated examples of SCCA or adenocarcinoma (Fig. 31.7). However, neuroendocrine differentiation is present in some examples of large cell carcinoma with genetic features similar to small cell carcinoma. Such large cell carcinomata with neuroendocrine differentiation can be thought of as a large cell variant of small cell carcinoma, a somewhat paradoxic designation. Subtypes of large cell carcinoma include giant cell carcinoma, clear cell carcinoma, and spindle cell carcinoma.
Large cell carcinoma. Most large cell carcinomas are thought of as very poorly differentiated squamous cell carcinomas or adenocarcinomas. (a) The neoplastic cells are very large with marked pleomorphism and show no definitive squamous or glandular differentiation. (b) At the same magnification, even larger neoplastic cells are noted in an example of the giant cell variant of large cell carcinoma.
Small cell carcinoma, like SCCA, is generally a central disease (Fig. 31.8) and is very strongly associated with smoking. Small cell carcinoma is a neuroendocrine lesion that almost invariably has metastasized by the time of diagnosis. It is named for its characteristic malignant cells that are smaller than malignant cells in other types of bronchogenic carcinoma. The malignant cells do not show squamous or glandular morphology, and small cell carcinoma is universally considered high-grade. Reflecting their neuroendocrine differentiation, immuno-histochemical staining will typically be positive for neural markers, for example, neurofilament, chromogranin, synaptophysin, and neuron-specific enolase (NSE). Ultrastructural analysis shows dense-core, membrane-bound neurosecretory granules. Common genes implicated in the pathogenesis of small cell carcinoma include p53 and RB.
(a) Small cell carcinoma, like squamous cell carcinoma, is typically located near the hilum; the white arrow indicates a bronchial lumen, and the tumor is the off-white lesion surrounding the lumen. The black arrow indicates a lymph node with apparent metastatic disease. (b) Microscopically, the malignant cells of small cell carcinoma show a very high nuclear/cytoplasmic ratio and characteristically show nuclear "molding," a term used to describe the appearance of nuclei being indented by neighboring cells. (c) Ultrastructurally, the neuroendocrine nature of the neoplasm is manifest by the presence of dense-core neurosecretory granules (arrow). (a): From Kemp et al. Pathology: the Big Picture, McGraw-Hill; 2008. (c): From Rosai and Ackerman's Surgical Pathology, 9th ed., Mosby-Elsevier, 2004.
Approximately 10% of cases of bronchogenic carcinoma show a combined pattern, usually of SCCA and adenocarcinoma, or of SCCA and small cell carcinoma.
CLINICAL CORRELATION 31.1
Cytologic analysis of sputum and/or bronchial brushings (Chaps. 18 and 19) can establish a diagnosis of bronchogenic carcinoma in 80%-90% of cases, potentially eliminating the need for diagnostic biopsy. However, false-positive diagnoses can be made, typically in the setting of pulmonary infarct, bronchiectasis, fungal/viral infection, lipid pneumonia, or following irradiation. With regard to the specific subtype of bronchogenic carcinoma, cytologic diagnosis agreement with histologic diagnosis (the "gold standard") is 70%-90%. The best agreement by such assays is for small cell carcinoma and for well-differentiated squamous cell carcinomas and adenocarcinomas.
Bronchogenic carcinoma begins as a focus of epithelial atypia progressing to a lumpy excrescence that elevates or erodes the epithelium. As the neoplasm grows, it can extend into the bronchial lumen to cause obstruction, penetrate the bronchial wall to invade peribronchial tissue, or grow within the parenchyma displacing other structures. Depending on the location within the respiratory tract, bronchogenic carcinoma can involve the pleural surface and spread through the pleural cavity or into the pericardium. In addition to metastasis through pleural fluid, bronchogenic carcinoma can metastasize via lymphatic and blood vessels. Most cases of bronchogenic carcinoma show lymph node metastases at the time of diagnosis; typical lymph nodes involved include tracheal, bronchial, and mediastinal. The most common sites of distant metastasis of bronchogenic carcinoma include the adrenals, liver, brain, and bone. The presentation of bronchogenic carcinoma is markedly variable and is discussed, along with staging of disease, in Chap. 32.