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Lung Tumors, A Multidisciplinary Database: Pathologic Type - Squamous Cell Carcinoma

Peter C. Fretz, B.S.
Jonathan H. Hughes, M.D., PhD
Peer Review Status: Internally Reviewed

Squamous cell carcinoma is a common form of lung cancer, accounting for approximately one-third of all cases of bronchogenic carcinomas. Unlike adenocarcinoma, it is strongly linked with a history of cigarette smoking. Its histogenesis may be related to chronic inflammation and injury of the bronchial epithelium, which leads to replacement of the normal ciliated columnar epithelium by a squamous epithelium. This transformation from a glandular epithelium to squamous epithelium is known as squamous metaplasia.

Histological and cytological studies have revealed a series of changes that occur over many years and represent a morphologic progression to bronchogenic carcinoma. Early changes include a loss of the ciliated columnar epithelium, basal cell hyperplasia, and the formation of a low columnar epithelium without cilia. These changes are followed by a squamous metaplasia. As cellular atypia develops and advances there is progression through mild, moderate and severe dysplasia to carcinoma in situ. Carcinoma in situ has no metastatic potential. However, once carcinoma in situ penetrates the basement membrane to involve the lamina propria, it is invasive carcinoma and capable of widespread dissemination. These progressive changes are similar to those that proceed the development of squamous cell carcinoma in the uterine cervix. This progressive sequence would suggest that it would be possible to detect abnormalities that are linked to bronchogenic carcinoma. However, unlike the cervix, there is no convenient test, like the Papanicolaou smear, to monitor this progression. Nor is it possible to identify with certainty which lesions will progress to carcinoma.

Most squamous cell carcinomas arise centrally from either the main, lobar or segmental bronchi and ulcerate through the mucosa into the surrounding lung parenchyma. Their central location also tends to produces symptoms at an earlier stage than tumors located peripherally. Although symptoms tend not to be specific, most commonly a non-productive cough, they stem from the involvement of vital structures at the hilar area of the lung. Most patients, however, are detected by a routine chest radiograph, before they are symptomatic. Larger tumors are associated with chest pain, loss of appetite, loss of weight and dyspnea on exertion.

Despite the fact that squamous cell carcinomas are rare in the periphery, they can cause a characteristic radiographical and clinical syndrome. They are the most common cause of the Pancoast or superior sulcus syndrome.

Endobronchial squamous cell carcinoma commonly leads to bronchial obstruction and post obstructive pneumonia. The common radiologic manifestations of squamous cell carcinomas result from the partial or total bronchial obstructions which leads to pneumonia or atelectasis. One characteristic radiographic sign is the "S sign of Golden," which is due to the inability of the upper lobe to completely collapse. The tumor causes the bulging of the minor fissure on the right leading to a sigmoid shape.

Gross Appearance
Squamous cell carcinomas tend to form firm, nonencapsulated, sharply circumscribed masses located in the main, lobar or segmental bronchi. On cut section, they are gray-white with a slightly granular and "dry" surface. If the cut surface glistens, a mucin producing tumor, such as adenocarcinoma or adenosquamous carcinoma, should be suspected. Like adenocarcinomas, they may induce a desmoplastic stromal response, producing a firm or rubbery texture.

Larger tumors often outgrow their vascular supply and may have central areas of hemorrhage, necrosis or cavitation. Necrotic areas tend to appear yellow and friable. Cavitation results from the central necrosis, and is seen in about 10% of all cases. Squamous cell carcinomas are the bronchogenic carcinomas most likely to cavitate.

Adjacent lung parenchyma may be firm and yellow-gray, which is suggestive of a post-obstructive pneumonia. Chronic bronchitis and centriacinar emphysema are also frequently seen in conjunction with squamous cell carcinomas.

Microscopic Features
In situ carcinomas appear as a thickened area of stratified squamous cells with hyperchromatic nuclei, with or without nucleoli and eosinophilic cytoplasm. The squamous cells do not show maturation towards the surface (loss of polarity). Intercellular bridges are prominent. The key feature of in situ carcinoma which distinguishes it from invasive squamous cell carcinoma is the presence of an intact basement membrane without invasion into the lamina propria.

Invasive squamous cell carcinoma exhibits similar features to those described above, but shows invasion through the basement membrane into the lamina propria. The histopathologic hallmark of invasion is the presence of a reactive mesenchymal proliferation of the submucosal stromal cells to the invading tumor, a phenomenon known as desmoplasia. Architecturally, invasive tumors tend to from irregularly shaped sheets and nests of cells. The shape and size of the neoplastic cells is polygonal to round with at least moderate amounts of cytoplasm. The nuclei tend to be irregularly shaped with coarsely clumped chromatin. There are three histologic features that are key to making the diagnosis:
    Keratin formation - seen as increased eosinophilia of individual cells.

    Keratin pearl formation - laminated whorls of eosinophilic cells.

    Intercellular bridges - fine parallel lines between cells, corresponding to desmosomes.
The presence of desmosomes or intercellular bridges is somewhat variable in squamous cell carcinomas and is most commonly seen in the more well differentiated tumors. When the bridges are not present, the squamous identity of the tumor may be suggested by the presence of uniform gaps between cells.

Squamous cell carcinomas are graded according to their degree of differentiation and designated as well, moderately, or poorly differentiated. Well differentiated tumors are recognized as exhibiting orderly stratification, obvious cellular bridges, and keratin pearl formation. In contrast, poorly differentiated squamous cell carcinomas are noted for their lack of keratinization and lack of intercellular bridges. Moderately differentiated tumors fall somewhere in between. Tumors are graded with respect to their least differentiated areas. The criteria for assigning grade are not precise and there are overlaps between the three categories.

The diagnosis and classification of squamous cell carcinomas are generally not aided by the use of routine histochemical stains. Occasionally, these tumors may form architectural patterns suggestive of glandular formation. In this case mucicarmine or periodic acid-Schiff with diastase stains are negative for cytoplastic mucin. Thus, certain immunohistochemical stains may also aid in making the diagnosis of squamous cell carcinoma. The two most useful are stains for keratins and epidermal growth factor receptor.

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