Histologically, and largely through an imperative of patient management, lung carcinomas are divided into two major types: non–small cell lung carcinoma and small cell lung carcinoma. About 75% to 80% of lung carcinomas diagnosed on bronchial and transbronchial biopsy fall into the non–small cell carcinoma category. The diagnostic process involves a number of steps: identification of neoplastic conditions and, in particular, malignancy, recognizing the tumor is carcinoma, separation of small cell carcinoma from other (non–small cell) carcinomas, and, where possible, making a specific histologic subtype diagnosis of a non–small cell carcinoma.

Small tissue biopsies from endoscopy may contain only tiny fragments of atypical epithelium or small numbers of atypical cells. The biopsy procedure may also cause substantial crush artifact and there may be intense inflammation associated with any neoplastic process. Thus there will be situations in reporting endoscopic biopsies when a confident diagnosis of carcinoma is not possible. Cytological atypia insufficient to diagnose carcinoma may require a “suspicious” report with recommendation for further biopsy. It may be difficult to confirm an atypical squamous epithelium that is invasive, and thus a differential diagnosis with squamous dysplasia/carcinoma in situ (see later and Chapter 6) is appropriate. Immunostaining for cytokeratins may, in some situations, confirm an apparently infiltrating cell population as epithelial and thus assist a diagnosis of carcinoma, provided the cells in question are neither from the nonneoplastic bronchial epithelium nor mucous glands.

The World Health Organization (WHO) lung tumor classification of non–small cell carcinoma (Table 3-1) is based on examination of the whole or a substantial part of the tumor. Limited material in small samples sometimes makes a definitive diagnosis of non–small cell lung carcinoma subtype impossible to render. For many of the categories in Table 3-1, this would always be the case. Thus it is important to realize it is sometimes inappropriate to subclassify non–small cell lung carcinoma on small biopsy material, and we often only make a diagnosis of non–small cell carcinoma, not otherwise specified.

Squamous cell carcinoma is the most frequently diagnosed cancer in endobronchial biopsy material. Specific diagnosis requires recognition of either intercellular bridges or keratinization in the tumor. Sometimes either of these features will be present only focally, and a careful search of all tumor foci is required to identify it. Tumor cells are frequently large with irregular nuclei and coarse chromatin, nucleoli may be present but are not usually prominent, and cytoplasm is often dense and eosinophilic. The tumor usually invades the bronchial mucosa in irregular but well-defined sheets and nests of tumor cells. A basaloid variant of squamous cell carcinoma shows smaller cells and less cytoplasm and, potentially, it may be confused with small cell carcinoma. In the basaloid variant, tumor cells may show palisading at the margin of tumor cell nests. Some squamous cell carcinomas show clear cell areas, and an endobronchial tumor in particular may exhibit a papillary architecture. Distinction between in situ and invasive squamous cell carcinoma in the bronchus may be difficult, especially when subepithelial stroma is scant or absent. In situ carcinoma tends
to exist in strips, whereas invasive tumor may demonstrate a more irregular pattern, comprising small islands or groups of cells, and a fibroblastic stromal reaction may be present. One further pitfall is the replacement of bronchial glands by extension of carcinoma in situ from the bronchial surface, mimicking invasive carcinoma and leading to misdiagnosis if the lobular architecture and occasional residual glandular cells are not recognized. Clinicopathologic correlation may help solve any problem, but repeat biopsy may also be necessary. In transbronchial lung biopsy, where more peripherally located squamous cell carcinoma invades lung parenchyma, nests of tumor cells may fill alveoli while the alveolar architecture remains intact. Squamous metaplasia with inflammatory reactive atypia in the lung periphery, occurring, for example, in the context of usual interstitial pneumonia or organizing diffuse alveolar damage may be misinterpreted as squamous cell carcinoma. As is always the case, knowledge of the clinical context, radiologic, and endoscopic findings should prevent misdiagnosis.

The peripheral location of adenocarcinomas makes them less often diagnosed in endoscopic biopsy material. Nonetheless, larger, more advanced adenocarcinomas may lie close to or involve an airway large enough to allow biopsy. A minority of adenocarcinomas probably originate in the proximal airways. The different patterns of invasive adenocarcinoma (acinar, papillary, micropapillary, and solid with mucin) may be appreciated in bronchial biopsies, although in practice acinar and papillary/micropapillary tumors are less common in such samples. In practice, given the tendency for many of these tumors to be relatively advanced and poorly differentiated, the solid pattern is most frequently found; occasionally the tumor has a cribriform architecture. Adenocarcinomas comprise a range of cell types depending on the architectural pattern present. Cells may be cuboidal, columnar, round, or oval. Cytoplasm may be eosinophilic, basophilic, or clear. A mucin stain may be extremely valuable in many instances, allowing identification of intracellular or extracellular mucin. Thyroid transcription factor-1 (TTF-1) and carcinoembryonic antigen (CEA) immunostaining also help to make a diagnosis of adenocarcinomas. Although the WHO classification of solid adenocarcinoma with mucin requires an arbitrary five cells with intracytoplasmic mucin vacuoles in each of two high-power fields, a more pragmatic approach is reasonable in bronchial or transbronchial biopsy specimens. The presence of mucin is sufficient for a presumptive diagnosis of adenocarcinoma, provided no other features are present to suggest an alternative. Mucin may be present in small vacuoles, finely
divided granules, or in goblet-type cells. Extracellular mucin in gland lumina may be seen, and care must be taken not to confuse mucin in the tumor with mucin from the nonneoplastic bronchial epithelium or bronchial glands also present in the sample. Lymphatic invasion within the bronchial mucosa is not uncommon and may be associated with nodal metastases; occasionally this lymphatic carcinoma may be the only tumor present in the biopsy specimen, so careful searching for such tumor is always worthwhile.

Bronchioloalveolar carcinoma (BAC) may be detected in transbronchial biopsy when alveolated lung is sampled. This is characterized by the growth of tumor cells, often columnar with apical snouts (Clara cells), around alveolar walls. Given that the WHO definition of BAC is of a tumor composed entirely of this pattern, with no evidence of stromal, vascular, or pleural invasion, it is clear that this diagnosis can never be made on bronchial or transbronchial biopsy samples. If tumor showing this so-called lepidic growth is found, a diagnosis of adenocarcinoma showing a BAC pattern in the sampled tissue should be made and efforts made to correlate pathology with radiology and clinical findings. It is important to mention the BAC pattern, if identified, because this is associated, at least in some cases, with a greater chance of response to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (Erlotinib, Gefitinib). Mucinous tumors, sometimes with mucin-filled goblet cells, may also exhibit this growth pattern (so-called mucinous BAC). In this instance the tumor cells may be present in small, sharply defined groups, lining only part of an alveolus. The presence of mucin, possibly in goblet cells, and the absence of ciliated cells helps distinguish this pattern of tumor from small reactive foci, for example foci of peribronchiolar metaplasia. In some cases of mucinous BAC, alveoli may contain either free mucin or many macrophages (muciphages) with foamy cytoplasm. Either of these features may appear in a transbronchial biopsy sample without any tumor cells. Clearly, carcinoma cannot be diagnosed in such an instance, but appropriate suspicion should be conveyed in the report.