42Figure 3.1a — Reactive Epithelial Cells, Bronchial Brushing [Pap Stain; High Power]. The majority of cells shown are bronchial respiratory epithelial cells, though they demonstrate various morphologies with various shapes and sizes. Some cells are round while other cells have a columnar or flask-like appearance. The nuclear-to-cytoplasmic ratios vary tremendously, with some cells appearing to have very little cytoplasm. The presence of pink cilia is evidence that these cells are benign, and is an important finding in the rounder cells that lack a distinct terminal bar.

Figure 3.1b — Reactive Epithelial Cells, Bronchial Brushing [Pap Stain; High Power]. The fragment of cells in this field appears markedly atypical. Some cells have extremely large nuclei with high-to-cytoplasmic ratios and cause concern for malignancy. However, the nuclear borders are round and regular and the chromatin pattern is bland. The most reassuring finding is the presence of pink cilia at the edge of some cells, as well as a distinct terminal bar at the bottom of the field. The presence of wispy, pink mucin in the background, which can coat cells and mimic cilia, is a confounding factor. Once some cells in the fragment are determined to be benign, the remainder of the cells can be dismissed as benign as well.

Figure 3.1c — Reactive Atypia, Bronchial Brushing [Diff-Quik Stain; High Power]. The center cell in this brushing demonstrates the dramatic reactive atypia occasionally encountered in pulmonary specimens. The adjacent glandular cells show focal nuclear overlap and enlargement with mild pleomorphism, but careful examination reveals preservation of apical cilia, suggesting benignity. Other findings in favor of a reactive atypia include the many background and epithelial-associated neutrophils and the smooth nuclear borders and even chromatin, even in the very large center cell. Dramatic atypia may be encountered after radiation and/or chemotherapy.

43Figure 3.1d — Reactive Atypia, Bronchial Brushing [Pap Stain; High Power]. Scattered cells stand out among the more reassuringly reactive ciliated glandular background in this brush specimen. These large cells are alarming, but have a chromatin pattern identical to their reactive neighbors as well as smooth nuclear borders and both appear to have a terminal bar with cilia, providing additional reassurance. Reactive bronchial cells may also have nuclear grooves, which are visible in some cells in this image. Bronchial irritation may result in cells with nuclei 10-20x larger than seen in normal bronchial cells.

Figure 3.2a — Reactive Atypia, Bronchial Brushing [Pap Stain; High Power]. This image shows the typical features of reactive bronchial respiratory cells, chiefly nuclear enlargement, pleomorphism, coarse chromatin with prominent nucleoli, and a “jumbled” arrangement. It is important to note the presence of a terminal bar and cilia on the atypical cells, which strongly favors reactive atypia. Scattered normal bronchial cells are present in the background for comparison. Reactive atypia may be seen in any condition that causes airway irritation, including infections, prior procedures, and chronic illness.

Figure 3.2b — Reactive Atypia, Bronchial Brushing [Pap Stain; High Power]. Numerous cells with swollen cytoplasm with a single vacuole are most striking in this image. While this may raise concern for adenocarcinoma, the background of reactive respiratory epithelium favors goblet cell metaplasia, a feature of chronic airway irritation. Goblet cell metaplasia may be particularly prominent in patients with cystic fibrosis.

44Figure 3.2c — Reactive Atypia, Bronchial Brushing [Pap Stain; High Power]. The dramatic nuclear enlargement of reactive bronchial epithelium is easily appreciated in this photograph. The nuclei in the center are several times larger than those at the periphery, and all display an open, coarsened chromatin with conspicuous nucleoli. There is a suggestion of a terminal bar in the center cells, but cilia are not easily appreciated. Immunohistochemistry cannot readily distinguish reactive from malignant cells, and careful attention to cellular details and context is crucial to avoid overdiagnosis of reactive changes as malignant.

Figure 3.3a — Reactive Atypia, Bronchoalveolar Lavage [Pap Stain; High Power]. Benign bronchial cells undergo morphologic alterations to a variety of injurious stimuli including inflammatory disease, various organisms, chemoradiation, inhaled irritants, asthma, toxic fumes (including oxygen toxicity), and pharmaceutical agents. These alterations typically include a variety of nuclear changes that mimic non–small cell carcinoma including enlargement, hyperchromasia, irregular and coarse chromatin distribution, and nucleolomegaly. Bronchial cilia may become either inconspicuous or lost altogether. In this image, marked nuclear enlargement along with the appearance of a distinct nucleolus (cell at the far left) is seen. Reddish cilia are barely perceptible. These changes may occur in single cells, and also in bronchial cell clusters.

Figure 3.3b — Reactive Atypia, Bronchoalveolar Lavage [Pap Stain; High Power]. In this example of reactive atypia, two cells exhibit marked nuclear enlargement, as well as coarse cytoplasmic vacuolization reminiscent of adenocarcinoma. Clinical history and radiologic findings are critical pieces of information needed to avoid a misdiagnosis of malignancy. In a patient such as this individual with acute and diffuse lung injury and the absence of a discrete lung mass, such cells should be interpreted with caution. Sequential bronchoalveolar lavage specimens may be necessary from such patients to assure a correct diagnosis.

45Figure 3.4a — Reactive Atypia, Fine Needle Aspiration [Pap Stain; High Power]. A cluster of reactive bronchial epithelial cells illustrates again the nuclear pleomorphism that typifies reactive atypia, but with the retention of smooth nuclear contours and a more open chromatin. The latter two features help to distinguish reactive cellular changes from malignant ones. Additionally, in reactive processes the cell-cell borders are maintained and the nuclei do not generally overlap. Architecturally, the streaming pattern and associated inflammatory cells also suggest a reactive rather than neoplastic process. Benign reactive atypia typically shows a spectrum of changes, rather than an abrupt transition.

Figure 3.4b — Reactive Atypia, Fine Needle Aspiration [Pap Stain; High Power]. At first glance, the central cluster of cells is concerning for adenocarcinoma, given the prominent nuclear atypia with conspicuous nucleoli and multiple mitotic figures (lower left of the central cluster). However, the overall architecture still displays the “streaming” quality that points to reactive, rather than malignant, changes. Additionally, the nuclear changes in the center cluster are similar to those in the bottom half of the image, where the benign nature of the cells is less in question. Chronic obstructive pulmonary disease can be a cause for airway irritation and reactive cellular changes.

Figure 3.4c — Reactive Atypia, Fine Needle Aspiration [Pap Stain; High Power]. The cells in this small cluster from a fine needle aspiration have a wide range of reactive nuclear changes, including variable size, shape, and presence/prominence of nucleoli. The cluster is small and isolated with a clean background. The smooth nuclear contours and even, open chromatin are also well displayed. Reactive changes may also be associated with systemic chemotherapy or radiation therapy for other malignancies.

46Figure 3.4d — Reactive Atypia, Fine Needle Aspiration [Pap Stain; High Power]. This image again illustrates the spectrum of changes seen in reactive cells, with enlarged nuclei with multiple nucleoli co-existing with smaller nuclei. Additional significant findings are that of an intra-epithelial neutrophil and other inflammatory cells within the cluster. The presence of inflammatory cells is reassuring of the reactive nature of the atypia, particularly if there are no other features of malignancy anywhere else in the specimen.

Figure 3.5a — Acute Pneumonia, Bronchoalveolar Lavage [Pap Stain; High Power]. Bronchoalveolar lavage fluid from a patient with acute pneumonia demonstrates abundant neutrophils, foamy pulmonary alveolar macrophages, and a few reactive pneumocytes. Exudative pneumonia, as seen here, is often a result of pyogenic bacteria, such as Streptococcus pneumonia.

Figure 3.5b — Acute Pneumonia, Bronchoalveolar Lavage [Pap Stain; High Power]. Acute exudative pneumonia, characterized by abundant neutrophils and scattered foamy histiocytes, as well as a cohesive cluster of atypical epithelial cells. These cells likely represent reactive pneumocytes that have sloughed off, but the degree of atypia could cause concern for carcinoma. Careful attention to the background and radiographic correlation are needed.

47Figure 3.5c — Acute Pneumonia, Bronchoalveolar Lavage [Pap Stain; High Power]. One cluster of reactive pneumocytes demonstrates variably enlarged nuclei with occasional nucleoli. The cells maintain a relatively low nuclear-to-cytoplasmic ratio with ample vacuolated cytoplasm. At times, it may not be possible to tell whether the changes represent pneumonia superimposed on a neoplasm, or dramatic reactive changes. In such cases, repeat sampling after resolution of the acute infection may be warranted.

Figure 3.6a — Acute Pneumonia, Bronchial Brushing [Pap Stain; High Power]. Brushings from a patient with acute pneumonia contain clusters and aggregates of surface epithelium with admixed acute inflammation [left panel]. The striking reactive changes in the epithelial cells are evident on the right. Despite the nuclear variability and prominent nucleoli, the nuclear borders remain smooth and the nuclear-to-cytoplasmic ratio is minimally increased.

Figure 3.6b — Acute Pneumonia, Bronchial Brushing [Pap Stain; High Power]. This image gives another view of the reactive changes that can be seen in a patient with pneumonia, particularly the increased nuclear size, open chromatin, and prominent nucleoli. Features that point to a reactive process include the smooth nuclear borders and the preserved cell-cell borders.

48Figure 3.6c — Acute Pneumonia, Bronchial Brushing [Pap Stain; High Power]. The striking atypia that can accompany an infectious pneumonia is again visible. The panel on the left contains a cohesive cluster of reactive bronchial epithelium, with vacuolated cytoplasm, enlarged nuclei, and nucleoli. The right hand panel has at the center-right a ciliated benign bronchial epithelial cell for comparison. This internal control shows how enlarged the reactive cells may be.

Figure 3.7 — Radiation-Induced Atypia, Bronchoalveolar Lavage [Pap Stain; High Power]. Radiation to the lung occurs as treatment for a variety of malignancies, for preconditioning prior to bone marrow transplantation, or less often from environmental exposure. Injury may be acute or chronic. Its effects on the cytomorphology of bronchial cells and pneumocytes are similar. These effects typically affect individual single cells, and include marked nuclear enlargement, often bizarre nuclear pleomorphism, intracytoplasmic and even intranuclear vacuolization (as seen in this cell), and multinucleation. Because cytoplasmic enlargement also occurs, the nuclear-cytoplasmic ratio is often preserved. Though not present in this image, cytoplasmic polychromasia is another manifestation of radiation-induced cellular atypia.

Figure 3.8a — Busulfan Treatment Effect, Bronchoalveolar Lavage [H&E Stain; High Power]. Busulfan is an alkyl sulfonate chemotherapeutic agent used to treat some hematopoietic malignancies and as a conditioning agent prior to bone marrow transplant. Interstitial pulmonary fibrosis (“busulfan lung”) is one toxic side effect seen in patients treated with busulfan. Busulfan can also cause atypical cytologic changes throughout the body, including nuclear enlargement, irregular nuclear borders, coarsely granular chromatin, macronucleoli, and cytoplasmic vacuolization. Seen here on a cell block preparation, atypical epithelioid cells with enlarged nuclei and an irregular chromatin pattern stand out in a background of macrophages and inflammatory cells.

49Figure 3.8b — Busulfan Treatment Effect, Bronchoalveolar Lavage [H&E Stain; High Power]. Cancer patients may be immunosuppressed and susceptible to lung infections. Bronchoalveolar lavages may be taken for the purposes of culture, with radiation and/or chemotherapy-induced changes seen in the specimen. If the history is unknown, these cells may be suspicious for dysplasia and/or malignancy. In this case, the atypical cell has a large amount of cytoplasm in spite of its enlarged nucleus with irregular borders and coarse chromatin.

Figure 3.8c — Chemotherapy-Induced Atypia, Biopsy [H&E Stain; High Power]. Reparative changes in the setting of chemotherapy may be associated with mass-like consolidation, and may have overlapping cytologic features with malignancy, as in this lung section. Epithelial cells are enlarged, with maintenance of the nuclear-to-cytoplasmic ratio (cytomegaly). There is nuclear pleomorphism and variable hyperchromasia; nucleoli are frequent. In some instances, mitoses may be readily identified. The interstitium contains a lymphoplasmacytic infiltrate with foamy histiocytes, and organizing pneumonia is present at the upper left. In contrast, the component cells of a malignant process manifest coarser chromatin and significant nuclear membrane irregularities; inflammation may be present, but the neoplastic cells predominate. An additional consideration is viral infection, from which chemotherapy effect cannot be confidently distinguished without viral diagnostic studies.