The two separate categories of neuroendocrine tumors in the World Health Organization (WHO) classification of lung tumors are small cell carcinoma and carcinoid tumor. A further important tumor type is a variant of large cell carcinoma: large cell neuroendocrine carcinoma. Non–small cell lung carcinomas of various types, as described in Chapter 3, may exhibit neuroendocrine differentiation at a molecular level as detected by immunohistochemistry or electron microscopy. This finding is of no proven clinical or pathologic importance, and these so-called non–small cell carcinomas with neuroendocrine differentiation are not discussed any further in this chapter. Table 4-1 lists those neuroendocrine carcinomas included in the WHO classification.

Small cell lung carcinoma comprises around 15% to 25% of all lung cancers. It is typically a central bronchogenic tumor and as such is frequently encountered in endoscopic biopsy specimens. The cells in small cell lung carcinoma are generally small, no more than the diameter of three small resting lymphocytes side by side, and they form sheets and masses of tumor infiltrating the bronchi. Tumor may infiltrate between the bronchial glands without destroying them. Cords of cells may dissect between collagen in the bronchial submucosa. Crush artifact is extremely common in this tumor type, but a similar change may occur in lymphoid tissue when it presents an important differential diagnosis. In uncrushed areas of tumor, which may require careful searching to find when sparse, tumor cells characteristically show nuclear molding but otherwise, the sheets of tumor cells generally show little architecture and may appear as a rather haphazard mishmash of small spindle or fusiform cells with a high mitotic and apoptotic rate. Nuclei are round, oval, or spindle shaped, and nuclear features are very characteristic, showing a fine granular (salt and pepper) or even featureless chromatin. Nucleoli are absent or, if present, almost always inconspicuous. Cytoplasm is generally scanty. Some cases show more epithelioid, cuboidal cells, and some architecture with trabeculae; an organoid pattern or rosette formation may be in evidence. Coagulative necrosis may be identified, particularly if the tumor sample is relatively large. Some small cell lung carcinoma cases show scattered larger cells with open nuclei, clumped chromatin, and even nucleoli; and occasionally, tumor giant cells may be scattered among typical small cells. Lymphatic invasion is not uncommon in the bronchial mucosa, and tumor cells frequently infiltrate, in a pagetoid fashion, the overlying surface epithelium, which may be of normal pseudostratified respiratory type, show squamous metaplasia or even squamous dysplasia, or carcinoma in situ. The bronchial mucosal stroma adjacent to small cell lung carcinoma often shows quite marked vascular proliferation, a feature that may, however, also be seen with non–small cell carcinomas. Occasionally small cell lung carcinoma may be found in conjunction with some form of non–small cell carcinoma, so-called combined small cell lung carcinoma. If both components are represented in the samples, such a diagnosis could be made on endoscopic biopsy material because there is no stipulation in the WHO classification of a required minimum proportion of the small cell lung carcinoma in combined cases. Small cell lung
carcinoma is a diagnosis that can be made very reliably and confidently on bronchial or occasionally transbronchial biopsy material stained by standard haematoxylin and eosin. Immunohistochemistry is not required to achieve a diagnostic accuracy of 90% and interobserver agreement among pathologists of 95%. These figures are better than those for non–small cell carcinomas, as described in Chapter 3. Where tumor is extremely crushed or there are some histologic features that raise the possibility of an alternative diagnosis, such as severe inflammation, lymphoma, or non–small cell carcinoma, immunohistochemistry may be useful. Confusion with benign lymphoid tissue may be compounded in cases that lack obvious mitotic activity or necrosis. Cytokeratin immunohistochemistry often shows paranuclear dot positivity, and this, together with negativity with CD45, may be sufficient to secure a diagnosis in a crushed sample, distinguishing small cell lung carcinoma from crushed benign or malignant lymphoid tissue. Small cell lung carcinoma expresses neuroendocrine markers in most cases; usually at least two of CD56, synaptophysin and chromogranin, are positive, but evidence of neuroendocrine differentiation as demonstrated by immunohistochemistry or electron microscopy is not required for a diagnosis of small cell lung carcinoma. Thyroid transcription factor-1 (TTF-1) is expressed in around 90% of cases. Neuroendocrine markers are obviously useful in differentiating small cell lung carcinoma from those nonneuroendocrine carcinomas, such as basaloid carcinoma and both basaloid and small cell variants of squamous cell carcinoma, which may mimic small cell lung carcinoma in small biopsy samples, especially when there is crush artifact. Useful adjuncts to diagnosis in this situation are the anti-HMW cytokeratin 34betaE12 and p63, which are not expressed in a range of neuroendocrine lung tumors but are frequently found in nonneuroendocrine carcinomas.