high proportion of patients with lung cancer. These molecular changes may play a central role in lung cancer pathogenesis. Two types of oncogenes have been identified: proto-oncogenes (which code for growth-promoting factors) and tumor suppressor genes (which code for factors having a negative regulatory effect on cell proliferation). A mutation in one of the paired alleles of a proto-oncogene can result in production of a protein with a growth-promoting effect such that a “dominant” behavior or effect would be observed. In contrast, both alleles of a tumor suppressor gene must be altered before the absence of the gene product would be clinically manifested as increased cell growth or malignant transformation. This requirement produces a “recessive” pattern of clinical expression.
Alterations in proto-oncogenes and tumor suppressor genes have been found in many patients with lung cancer.
Examples of specific alterations in proto-oncogenes that have been identified in lung cancer include mutations in the epidermal growth factor receptor (EGFR), activin receptor-like kinase (ALK), and KRAS families of dominant oncogenes. A variety of mutations in recessive tumor suppressor genes also have been identified, including the retinoblastoma (rb) and p53 genes. In addition, deletion of genetic material from chromosome 3p (the short arm of chromosome 3) has been recognized in lung cancer, and it is thought that deletion may involve loss of one or more tumor suppressor genes. Efforts to elucidate the pathobiology of oncogenes in lung and other cancers constitute an exploding area of intense investigation that is beyond the scope of this textbook. Readers are referred to excellent review articles in the Suggested Readings at the end of this chapter. Importantly, the presence of some of these alterations affects treatment choices, as discussed in Chapter 21.
Pathology
The term bronchogenic carcinoma is often used interchangeably with the term lung cancer, implying that lung cancers arise from bronchi or bronchial structures. Many cancers do originate within airways, but other tumors arise in the periphery of the lung and may not necessarily originate in an airway. This section focuses on the currently accepted classification of lung cancer, which was updated in 2015 and then again in 2021, and summarizes what is known about the behavior patterns of the various types of tumors. Of note, whereas older classification schemes of lung cancer relied exclusively upon microscopic examination of stained specimens, immunohistochemistry and genetic analysis now play a central role in characterizing lung malignancies.
Most lung cancers fall within one of four histologic categories: (1) squamous cell carcinoma, (2) adenocarcinoma, (3) large-cell carcinoma, and (4) small-cell carcinoma (now considered a subcategory of neuroendocrine tumors). Within each histologic category are several subcategories that, for our purposes, are less important. Of note, nearly 15% of lung cancers are considered “other non–small-cell” tumors, a category that includes malignancies too anaplastic to permit further subtyping, as well as rarer variants that are not discussed here.
Major histologic categories of lung cancer:
1.Squamous cell carcinoma
2.Adenocarcinoma
3.Large-cell carcinoma
4.Small-cell carcinoma (subcategory of neuroendocrine tumors)
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A major distinction to make is between small-cell lung carcinoma (SCLC) and all the other cell types, which are grouped together as non–small-cell lung carcinoma (NSCLC). The importance of this distinction relates to the propensity of small-cell carcinoma for early clinical and subclinical metastasis, which affects the approaches to staging and treatment of this tumor compared with those of all the other cell types. Within non–small-cell carcinomas, a second important distinction is between squamous cell carcinoma and other non–small-cell carcinomas, especially adenocarcinoma, because of differences in responsiveness to certain drugs, such as EGFR tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors (discussed in Chapter 21).
Each of the four major categories of lung cancer is associated with cigarette smoking, but the statistical association between smoking and the individual cell types is strongest for squamous cell carcinoma and small-cell carcinoma, which are seen almost exclusively in smokers. Even though smoking also increases the risk for adenocarcinoma and large-cell carcinoma, these cell types also occur with some regularity in nonsmokers.
Squamous cell carcinoma
Formerly the most common histopathologic type encountered, squamous cell tumors currently account for approximately only 20% to 25% of all primary lung cancers. These malignancies originate within the epithelial layer of the bronchial wall, in which a series of progressive histologic abnormalities result from chronic or repetitive cigarette smoke–induced injury.
Initially, there is metaplasia of normal bronchial columnar epithelial cells, which are replaced by squamous epithelial cells. Over time these squamous cells become more and more atypical in appearance until a well-localized noninvasive carcinoma (i.e., carcinoma in situ) develops. Eventually the carcinoma extends beyond the bronchial mucosa and becomes frankly invasive. After the tumor reaches this stage, it generally comes to eventual clinical attention by producing either symptoms or radiographic changes. In some cases, detection of the carcinoma is made at the earlier in situ stage, usually by recognition of the malignant cells in a specimen of sputum obtained for cytologic examination or by biopsy of grossly abnormal-appearing bronchial mucosa during bronchoscopic evaluation undertaken for other reasons.
Specific histologic features of squamous cell carcinoma are common and point the pathologist to this diagnosis. These tumors are characterized by the visible presence of keratin, “squamous pearls,” and intercellular desmosomes or bridges (Fig. 20.1).
FIGURE 20.1 Photomicrograph of squamous cell carcinoma. Arrows outline a
“keratin pearl,” a characteristic of squamous cell carcinoma.
Squamous cell carcinomas tend to be located in relatively large or proximal airways, most commonly at the subsegmental, segmental, or lobar level. With growth of the tumor into the bronchial lumen, the airway may become obstructed. The lung distal to the obstruction frequently collapses (becomes atelectatic), and a postobstructive pneumonia may develop. Sometimes a cavity develops within the tumor mass; this finding of cavitation is much more common with squamous cell than with other types of bronchogenic carcinoma.
Features of squamous cell carcinomas:
1.Generally arise in proximal airways
2.May cause airway obstruction, leading to distal atelectasis or pneumonia
3.May cavitate
4.Intrathoracic spread rather than distant metastases
Spread of squamous cell carcinoma beyond the airway usually involves (1) direct extension to the pulmonary parenchyma or other neighboring structures or (2) invasion of lymphatic vessels, with spread to local lymph nodes in the hilum or mediastinum. These tumors have a tendency to remain within the thorax and cause problems by intrathoracic complications rather than by distant metastasis. Although the stage at presentation is the primary determinant of survival, some studies suggest the overall prognosis in terms of 5-year survival is better for patients with squamous cell carcinoma than for those with other cell types.
Adenocarcinoma
Adenocarcinoma has surpassed squamous cell carcinoma as the most frequent cell type, accounting for approximately 50% of primary lung tumors. Because most adenocarcinomas occur in the lung periphery, it is much harder to relate their origin to the bronchial wall. At present, these tumors are believed to arise at
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the level of bronchioles or alveolar walls. Adenocarcinomas sometimes appear at a site of parenchymal scarring that is either localized or part of a diffuse fibrotic process.
Adenocarcinoma is the most common type of lung cancer to develop among nonsmokers. Nearly 18% of lung adenocarcinomas are diagnosed in nonsmokers, versus less than 2% of squamous cell carcinomas and less than 1% of small-cell carcinomas. Although the risk factors are not well understood, secondhand smoke exposure may be a contributing factor in some cases. A link between human papillomavirus and adenocarcinoma of the lung has been hypothesized but not definitively established.
The characteristic appearance defining adenocarcinoma is the tendency to form glands, and in many cases produce mucus (Fig. 20.2). When the malignant cells seem to grow and spread along the preexisting alveolar walls, almost as though they were using the alveolar wall as scaffolding for their growth, the tumors are described as having a lepidic pattern of growth (Fig. 20.3). The term lepidic carcinoma is now used for an invasive carcinoma with this growth pattern, but a similar growth pattern is also seen in earlier, noninvasive tumors that are classified as either adenocarcinoma in situ or minimally invasive adenocarcinoma. Prior to the 2015 WHO classification of lung tumors, these different tumor types that exhibit lepidic growth were labeled as bronchioloalveolar carcinoma, but this term has been eliminated from the current classification system.
FIGURE 20.2 Low-power photomicrograph of adenocarcinoma of lung. Malignant
cells form gland-like structures.
FIGURE 20.3 High-power photomicrograph showing lepidic growth of tumor
along preexisting alveolar walls. This pattern can be seen in some cases of
adenocarcinoma as well as in adenocarcinoma in situ and minimally invasive
adenocarcinoma.
The usual presenting pattern of adenocarcinoma is a peripheral lung nodule or mass. Occasionally, the tumors arise within a relatively large bronchus and therefore may become apparent clinically because of complications of localized bronchial obstruction, as seen with squamous cell carcinoma. The lepidic subcategory can manifest in several ways: as a nodule or mass lesion, as a localized infiltrate simulating a pneumonia, or as widespread parenchymal disease.
Although adenocarcinoma may spread locally to adjacent regions of lung or to pleura, it also has a propensity for hilar and mediastinal lymph node involvement and distant metastatic spread. Like smallcell carcinoma, it spreads to liver, bone, central nervous system, and adrenal glands. In comparison with small-cell carcinoma, however, adenocarcinoma is more likely to be localized at the time of presentation, particularly when it manifests as a solitary peripheral lung nodule.
Features of adenocarcinomas:
1.Often manifest as a solitary peripheral pulmonary nodule
2.May arise in an old parenchymal scar
3.Generally localized when presenting as a peripheral lung nodule
4.Spread to hilar and mediastinal nodes and to distant sites
Large-cell carcinoma
Large-cell carcinoma accounts for approximately 2% of all lung cancers. Essentially a diagnosis of exclusion, it is the most difficult carcinoma to describe microscopically because the tumors often are defined by the characteristics they lack—that is, the specific features, both by light microscopy and histochemistry, that would otherwise classify them as one of the other three cell types. Microscopically,
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they appear as collections of large polygonal cells with prominent nucleoli and a moderate amount of cytoplasm.
The behavior of these tumors is similar to that of adenocarcinoma. They often appear in the periphery of the lung as mass lesions, although they tend to be somewhat larger than adenocarcinomas. Their natural history is also similar to that of adenocarcinoma in terms of both propensity for spread and overall prognosis.
Small-cell carcinoma
Small-cell carcinoma, constituting 10% to 15% of all lung cancers, is classified as a neuroendocrine tumor, along with several other less common tumors. Like squamous cell carcinomas, small-cell carcinomas are strongly associated with cigarette smoking and generally originate within the bronchial wall, most commonly at the level of the proximal airways. Small-cell carcinomas, like other lung cancers, originate from a pluripotent stem cell. The eventual cell type then depends on the pattern and degree of differentiation from this precursor cell. Molecular and chromosomal studies have shown that more than 90% of small-cell carcinomas demonstrate deletions on the short arm of chromosome 3 (3p).
In small-cell carcinoma, the malignant cells appear as small, darkly stained cells with sparse cytoplasm (Fig. 20.4). Local growth of the tumor often follows a submucosal pattern, but the tumor quickly invades lymphatics and submucosal blood vessels. Hilar and mediastinal nodes are involved and enlarged early in the course of the disease and frequently are the most prominent aspect of the radiographic presentation.
FIGURE 20.4 High-power photomicrograph of small-cell carcinoma. Malignant
cells have irregular, darkly stained nuclei and sparse cytoplasm.
Features of small-cell carcinomas:
1.Generally arise in proximal airways
2.Commonly associated with hilar and mediastinal node involvement
3.Manifest early, distant metastatic disease
Due to the characteristic rapid dissemination, most small-cell carcinomas have already metastasized to distant sites at the time of diagnosis. Distant disease, which may be clinically occult at the time of presentation, often affects the brain, liver, bone (and bone marrow), and adrenal glands. It is this propensity for early metastatic involvement that gives small-cell carcinoma the worst prognosis among the four major categories of bronchogenic carcinoma. Table 20.1 summarizes the distinguishing features of each cell type and reiterates many of the points discussed in this chapter.
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