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Common Differential Diagnostic Issues in Lung Cytopathology: 3 Case Reports and a Review

Fanaroff, Rachel MD; Legesse, Teklu B. MD; Geisinger, Kim R. MD

Author Information
doi: 10.1097/PCR.0000000000000443
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Abstract

PATIENT 1

A 78-year-old woman with a 16-pack-year smoking history presented to the emergency department for fever, chest pain, and abdominal pain. A computed tomography scan was performed, which demonstrated a subcentimeter ground-glass opacity in the right upper lobe that was concerning for infection. The patient was prescribed an antibiotic and recommended to receive follow-up imaging. On rescan 3 months later, the area of opacification had grown to 1.4 cm and was partially solid.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed, and smears revealed a few groups of monomorphic, slightly enlarged cells with nuclear contour irregularities and overlap. The background was largely paucicellular. A diagnosis of adenocarcinoma was rendered.

Subsequently, the patient underwent a wedge resection of her nodule that showed a well-differentiated adenocarcinoma that showed a predominantly lepidic pattern with a smaller acinar component

Reactive Bronchial Cells and Pneumocytes Versus Well-Differentiated Lung Adenocarcinoma

Adenocarcinoma represents the most common subtype of lung carcinoma, accounting for approximately 40% of primary lung carcinomas.1,2 Adenocarcinomas are also the most common lung carcinoma in patients who have never smoked.3

There is significant diversity in cytologic and histologic morphology, with the appearance ranging from relatively bland-appearing lepidic-predominant carcinomas, as in this case, to poorly differentiated tumors that require ancillary testing for definitive identification.4–6 In the latter circumstance, the diagnosis of carcinoma is made with ease. However, when the neoplastic cells are well-differentiated, difficulties arise in distinguishing tumor cells from reactive bronchial cells and pneumocytes. Similar challenges may occur in distinguishing low grade tumor cells from macrophages, especially in washing and sputum specimens.

Reactive Bronchial Cells and Pneumocytes

Bronchial cells and pneumocytes are normal components of the lower respiratory tract. Bronchial cells are present more proximally and line the bronchi and bronchioles. Pneumocytes line the alveoli and are categorized as either type I or type II. Type I pneumocytes are thin epithelial cells that line the portions of the alveolus involved in gas exchange, whereas type II pneumocytes are cuboidal, produce surfactant, and have regenerative capacity for the type I pneumocytes when the epithelium is damaged.7

In cytologic preparations, benign bronchial cells are usually readily recognized by their columnar shape; small round, basally oriented nucleus; and their cilia, which are present at the apical surface and project from a dense, opaque terminal bar. However, they can show profound morphologic changes in response to radiation, chemotherapy, infection, inhalational exposures, interstitial lung disease, infarction, or other injurious processes.8–10 These changes occur on a spectrum, ranging from mild nuclear enlargement with retained nuclear-to-cytoplasmic ratio to marked pleomorphism, including concerning nuclear changes such as profound increase in size, contour irregularities, overlap, and macronucleoli (Fig. 1)8,9,11,12 Despite these alterations, evidence of benignity may be gleaned from the fine, even chromatin texture, streaming architecture, and, most importantly, cilia and underlying terminal bar.8–11 Both atypical and obviously benign-appearing cells in a single group are particularly helpful, as it manifests a spectrum of change.13 Although cilia may become inconspicuous or degenerated in robust reactive processes, if present, they are reassuring.9,10,14 The presence of similar changes and degree of atypia in the cells with cilia and without cilia is also a reassuring feature. The background appearance of plentiful neutrophils also supports a reactive response.9

F1
FIGURE 1:
Reactive bronchial cells. Although individual cells appear worrisome for malignancy, the spectrum of change, presence of cilia, smooth rounded nuclear contours, and preserved cohesion are reassuring. A, Papanicolaou stain, high power. B, Diff-Quik stain, high power.

Pneumocytes in cytologic preparations are nearly always type II pneumocytes; type I pneumocytes are not readily identified on smears or in cell block preparations unless present in larger tissue fragments.8 Type II pneumocytes are usually identified in bronchoalveolar lavage, bronchial washings, and brushings and less commonly in fine-needle aspiration samples. They appear as round to cuboidal vacuolated cells, which may be present as single cells or in medium to large aggregates; they may be confused for macrophages.15 As they serve as reserve cells for the type I pneumocytes, type II pneumocytes show hyperplasia when the epithelium is injured.8 Similar to bronchial cells, type II pneumocytes can have significant reactive atypia, including nuclear enlargement and prominent nucleoli.9 Their surfactant vacuoles may additionally be confused for the mucin vacuoles of adenocarcinoma (Fig. 2).8 However, reactive pneumocytes usually retain their nuclear-to-cytoplasmic ratios and smooth nuclear contours. When seen in clusters, their borders may be scalloped, as opposed to the community borders seen in adenocarcinoma.14 Attention to the background cellularity is particularly helpful in distinguishing reactive pneumocytes from adenocarcinoma, as reactive pneumocytes are often seen in the presence of neutrophils and other inflammatory cells.9 In addition, they are usually found in limited numbers, and one should be wary of dismissing numerous atypical cells as reactive pneumocytes.

F2
FIGURE 2:
Reactive pneumocytes. A cluster of reactive pneumocytes shows vacuolated cytoplasm and scalloped borders. Further, the presence of cytoplasm at the aggregate’s periphery is more in keeping with benign glandular cells.

Well-Differentiated Lung Adenocarcinoma

While a histologic grading system for lung adenocarcinomas has not been established, a spectrum of atypia is seen.16 So-called well-differentiated lung adenocarcinomas are composed of bland-appearing neoplastic cells. On resection, these may be present in a lepidic predominant architectural pattern.6,17,18

On cytologic specimens, the tumor cells are present singly, in sheets, and in 3-dimensional clusters. Their nuclei are frequently eccentrically placed, round, and with a single, prominent nucleolus.8,18 Tumors ultimately identified as well-differentiated at resection show smaller nuclear size, smoother nuclear contours, less conspicuous nucleoli, and finer chromatin compared with their high-grade counterparts (Fig. 3).19,20 In well-differentiated tumors, the cytoplasm can be abundant and delicate and may be vacuolated, but the cytoplasmic characteristics vary.8,11,20

F3
FIGURE 3:
Well-differentiated adenocarcinoma. The tumor cells with acentric nuclei and abundant flocculent cytoplasm manifest disrupted polarity. The background is without inflammation or debris. The cell block shows a neoplastic population of well-differentiated tumor cells. The resection specimen showed an invasive well-differentiated tumor with a predominant lepidic pattern. A, Papanicolaou stain, high power. B, Cell block, hematoxylin-eosin stain, high power. C, Resection, hematoxylin-eosin stain, medium power.

Compared with reactive bronchial cells and pneumocytes, the tumor cells of well-differentiated adenocarcinoma show increased clustering and formation of 3-dimensional groups.8 Profound nuclear enlargement may be helpful in distinguishing adenocarcinoma from benign entities, although the morphometric data are mixed.11,14,21,22 Nuclear contour irregularities, prominent nucleoli, and the absence of cilia are also useful in differentiating tumor cells from reactive processes.8,9,23 Of note, reactive processes may show increased pleomorphism compared with well-differentiated adenocarcinoma, which can appear monomorphic.24 A large number of atypical cells in a relatively clean background is also suggestive of a malignant process.18,25 A dual-cell population, in which there are 2 distinct cell morphologies as opposed to a spectrum of change, supports a diagnosis of adenocarcinoma.8 Finally, careful attention to the patient's clinical history is essential; the presence of a mass and absence of infectious etiology or lung injury should raise concern for a neoplastic process even if the cells are relatively bland in appearance.25

PATIENT 2

A 68-year-old man with a history of mantle cell lymphoma status post chemotherapy and stem cell transplant was found to have an enlarging right lower lobe lesion on routine surveillance. The mass was noted to be 3.7 cm in greatest dimension and spiculated, with central cavitation. There was ipsilateral mediastinal adenopathy. Endobronchial ultrasound-guided transbronchial needle aspiration was performed to interrogate the mass.

Smears of the lesion demonstrated few viable, keratinizing cells with abundant necrotic debris. Special stains for fungal and mycobacterial organisms were negative. Although the keratinizing cells and debris were morphologically concerning, the case was categorized as atypical due to paucicellularity of viable cells.

Because the EBUS-TBNA was indeterminate for malignancy, a wedge biopsy was performed. This demonstrated a 3.2-cm necrotizing granuloma with no evidence of malignancy.

Atypical Squamous Metaplasia Versus Squamous Cell Carcinoma

Squamous cell carcinoma is the second most common lung carcinoma, representing approximately 20% of lung carcinomas.26 There is a strong association with cigarette smoking and other inhalational exposures.27

Similar to adenocarcinoma, squamous cell carcinoma varies in appearance, with some tumors appearing more well-differentiated than others.28 Squamous lesions exist on a morphologic continuum, with many arising from transformation of the usual bronchial mucosa. Following an insult, the bronchial mucosa undergoes a series of molecular alterations leading to squamous metaplasia.29 This, in turn, may lead to squamous dysplasia and, ultimately, to invasive squamous cell carcinoma.7,30 Because these preinvasive and invasive lesions exist on a spectrum, diagnostic confusion may arise in differentiating a squamous cell carcinoma from an atypical squamous metaplastic process.

Atypical Squamous Metaplasia

Squamous metaplasia is the first in a series of alterations that occur in the carcinogenesis of squamous cell carcinoma. It occurs in response to a variety of injurious processes, including cigarette smoke, fungal infection, chemoradition, and infarction.8 Although squamous metaplasia is a benign, reactive process, the continued accumulation of mutations may lead to dysplasia and, in some cases, the progression to in situ carcinoma and invasive carcinoma.29

In cytology preparations, squamous metaplastic cells have dense cytoplasm, which may show orangeophilia.9 The nuclei are small, round, and regular. The nuclear-to-cytoplasmic ratio is preserved.9 However, in the setting of significant insult, there may be marked atypia, including increased nuclear-to-cytoplasmic ratio and nuclear hyperchromasia (Fig. 4).25 Such changes may be seen adjacent to cavitary infections, as in this case, which may have the radiologic appearance of a carcinoma with cavitation. These are frequently fungal infections.8 Instrumentation can lead to irritation and necrosis, which appear on cytologic preparations as abundant keratinizing cells with degenerating nuclei; without appropriate caution, this may be overinterpreted as well-differentiated squamous cell carcinoma.14 Features supportive of benignity include smudgy chromatin, fewer single cells, and absent nucleoli.31

F4
FIGURE 4:
Atypical squamous metaplasia. On smears, the atypical metaplastic cells have high nuclear-to-cytoplasmic ratios, irregular nuclear contours, and, in some, orangeophilic cytoplasm in a background of necrotic debris. The cell block shows mild atypia. Nonetheless, the resection specimen showed a necrotizing granuloma. A and B, Papanicolaou stain, high power. C, Resection, hematoxylin-eosin stain, medium power.

Squamous Cell Carcinoma

Squamous cell carcinoma shows marked variation in morphology, depending on the degree of differentiation. In well-differentiated tumors, the lesional cells form intercellular bridges, have abundant eosinophilic cytoplasm, and may have individual cell keratinization.30 They can form keratin pearls and have variable architectural patterns.7 Moderately or poorly differentiated squamous cell carcinomas have lost these morphologic indications of their squamous differentiation. They show the features seen in other high-grade carcinomas, including high nuclear-to-cytoplasmic ratios and marked pleomorphism.7 In such cases, the use of immunohistochemical staining is useful in distinguishing squamous cell carcinoma from other tumor types. Immunostains for p40 and TTF-1 are considered optimal as an initial panel for distinguishing squamous cell carcinoma from adenocarcinoma; squamous cell carcinoma is positive for p40 and negative for TTF-1, whereas adenocarcinoma is generally negative for p40 and positive for TTF-1.18 Squamous cell carcinoma was historically classified by subtype and degree of keratinization, but these features are not associated with survival and so are no longer in use.28

The cytomorphology of squamous cell carcinoma in the lung is similar to that in other organ sites. Well-differentiated tumors have abundant, dense cytoplasm, which is classically robin's egg blue on Romanowsky stain.8 On Papanicolaou stain, the cytoplasm may be orangeophilic or teal.8,32 Like many other malignancies, the nuclei are hyperchromatic with irregular nuclear contours.9 The tumor cells may be polygonal, elongated, or present in other bizarre forms. They may be seen as single cells or in streaming groups.8,32 Intercellular bridging, which is better visualized on cell block preparations, may also be present.9 When in groups, squamous cell carcinoma can form branching structures, as compared with the 3-dimensional clusters of adenocarcinoma.8 As discussed previously, moderately or poorly differentiated tumors lack the features that indicate their squamous origin and thus resemble high-grade carcinomas of other etiologies. Because of their unequivocally malignant appearance, these high-grade carcinomas are unlikely to be confused for atypical squamous metaplasia (Fig. 5).31

F5
FIGURE 5:
Squamous cell carcinoma. The tumor cells show marked nuclear hyperchromasia and pleomorphism. Orangeophilia, although not always present, is helpful in determining squamous differentiation of the tumor cells, as is dense, homogeneous cyanophilic cytoplasm. The cell block reveals cohesive groups of cells with abundant cytoplasm and intracellular bridging. A and B, Papanicolaou stain, high power. C, Cell block, hematoxylin-eosin stain, medium power.

Compared with atypical squamous metaplasia, squamous cell carcinoma is more frequently seen as single cells.31 Dyshesive, irregular cells with orangeophilia to indicate keratinization strongly suggest a malignant process.9 Prominent nucleoli may be seen in robust reactive or reparative processes, but are more characteristic of squamous cell carcinoma.31 Although squamous cell carcinoma is often seen in a background of granular necrosis, care should be taken when there are few viable cells or the cells are poorly preserved, as these features may also be seen in serious fungal infections or other exuberant reactive processes.8 The radiologic finding of a mass is useful, but a history of smoking is not; both squamous metaplasia and squamous cell carcinoma are associated with smoking.7

PATIENT 3

A 72-year-old man with a history of prostate cancer, emphysema, and coronary artery disease was found to have a 2.0-cm spiculated right upper lobe nodule. Endobronchial ultrasound-guided transbronchial needle aspiration was performed and identified the nodule as a primary lung adenocarcinoma. Because of his extensive chronic obstructive pulmonary disease, the patient was not a surgical candidate and thus received radiation therapy.

A follow-up scan approximately 18 months later demonstrated an area of nodularity in the radiation field, with increased uptake on positron emission tomography scan. A transthoracic core needle biopsy with touch preparation was performed under interventional radiology guidance to assess for disease recurrence.

The touch preparations and core needle biopsy demonstrated an overall paucicellular specimen of atypical epithelial cells with preserved nuclear-to-cytoplasmic ratio, vacuolization, and a relatively clean background. Although a diagnosis of adenocarcinoma was considered, the findings were ultimately determined to be related to the patient's prior radiation therapy.

Therapy-Related Atypia Versus Recurrent or Persistent Non–Small Cell Lung Carcinoma

The treatment of lung cancer depends on the histologic subtype, with the most important distinction being between non–small cell carcinoma and small cell carcinoma. Small cell carcinoma is often metastatic at the time of diagnosis and is usually treated with systemic chemotherapy.8 Non–small cell carcinoma may be treated with surgery, chemotherapy, radiation, or a combination thereof.33,34 In these circumstances, EBUS-TBNA may be used to monitor for treatment response.35–37 However, because the treatments lead to morphologic changes in both the tumor cells and benign lung parenchyma, the distinction between therapy-related atypia and persistent or recurrent carcinoma may prove challenging.

Therapy-Related Atypia

The treatment of lung cancer depends on the histologic subtype, stage of disease, and performance status of the patient. For early-stage lung cancers and in patients with adequate physiologic reserve, surgical resection may be appropriate. Surgical resection specimens include wedge resections, lobectomies, and, less frequently, pneumonectomies.7 Systemic or targeted treatment modalities may be offered adjuvantly, neoadjuvantly, or, if the patient is not a surgical candidate, as the primary therapeutic option.38 Radiation therapy causes DNA damage directly and indirectly, leading to apoptosis, necrosis, and prevention of mitosis.38,39 Like radiation therapy, traditional chemotherapy regimens have a variety of mechanisms, all of which aim to destroy or prevent the growth of tumor cells. With the advent of molecular testing, therapies have also been developed that specifically target different mutations.8,40

Although treatment may be effective in eradicating tumor cells, radiation in particular causes profound morphologic changes in the benign cells. These changes are seen within weeks of initiation of therapy and may resolve following cessation of treatment or persist long after.13,14,25 Bronchial cells and pneumocytes are affected in similar ways. The nuclei enlarge and develop prominent nucleoli or smudgy hyperchromasia, but may also become small and degenerated.9,14 The cytoplasm may be foamy or have a 2-tone appearance. Vacuolization of the nucleus and cytoplasm is common.8,9,13,14 The cells can become significantly enlarged and have marked pleomorphism with bizarre forms and multiple nuclei (Fig. 6). Unlike tumor cells, cells with therapy-related change show aggregates that show a repair-like, pulled architecture.14,25 They may also be present as highly atypical single cells.13,25 Importantly, regardless of their worrisome appearance, these benign cells have a preserved nuclear-to-cytoplasmic ratio.9,13 Patient history and imaging findings are of paramount importance, although mass-like areas of consolidation or ground-glass areas of opacification may be seen following radiation.7,9 The changes of chemotherapy are comparable to those seen with radiation.8,13 However, following surgery, the reactive changes seen in bronchial cells and pneumocytes are similar to morphologic changes present in more typical circumstances, such as infection.8,14,31

F6
FIGURE 6:
Therapy-related atypia. Following therapy, particularly radiation, benign cells become enlarged, but maintain their low nuclear-to-cytoplasmic ratios. Note the smooth nuclear outlines. A resection specimen shows the histologic correlate of these cells. Further, contrast the presence of altered and normal polarity in the malignant and benign cells, respectively. A, Diff-Quik stain, high power. B, Papanicolaou stain, high power. C, Resection, hematoxylin-eosin stain, medium power.

Recurrent or Persistent Non–Small Cell Lung Carcinoma

Endobronchial ultrasound-guided transbronchial needle aspiration is a minimally invasive method of assessing recurrence or persistence of non–small cell carcinoma in lymph nodes and, to a lesser extent, in the treated tumor bed.35–37,41 However, EBUS-TBNA following surgery or chemoradiation is often more complicated than the initial diagnosis and staging of lung tumors. For the operator, the procedure may be technically challenging because of treatment-related fibrosis.42,43 Other complicating factors include abundant necrosis or scarring and few viable tumor cells, which could lead to undersampling of the lesion.42 Nonetheless, appropriate resampling can lead not only to a diagnosis, but also to material for additional studies.41,44

The cytologic appearance of non–small cell carcinoma compared with therapy-related atypia depends on the histologic subtype of the treated tumor (Fig. 7). However, regardless of the tumor type, the cells show an increased nuclear-to-cytoplasmic ratio.10 The nuclei have irregular contours and coarse, rather than smudgy, chromatin. They may not show degenerative changes.8,13,14 Assuming an adequate sample, the cells of malignant processes are also usually more numerous than those of therapy-related atypia.8,13 If the differential diagnosis includes a squamous cell carcinoma, the cytoplasm should be dense, rather than vacuolated or foamy.13 Close attention to the clinical history and radiologic impression is imperative in these circumstances.10

F7
FIGURE 7:
Poorly differentiated carcinoma. This adenocarcinoma was poorly differentiated, requiring stains to determine its origin. Note the nuclear crowding, large nuclear size, and irregular nuclear contours, in contrast with the benign bronchial cells in the top left of the image.

CONCLUSIONS

These 3 cases illustrate both the complexity of pulmonary cytology and also the careful consideration the cytopathologist must take in evaluation of these specimens. Cases 1 and 3 emphasize the role cytopathology plays in guiding appropriate treatment and preventing overtreatment. Case 2 highlights the limitations of cytopathology; in some circumstances, a definitive diagnosis cannot be rendered, and a diagnostic category of “atypical cells present” with a descriptive comment about the morphologic differentials and a recommendation for repeat sampling may be appropriate. Depending on the clinical situation, a surgical intervention may also be the appropriate tool for diagnosis. In addition, many cytology samples are also accompanied by small biopsies or cell block material, and correlation with the histologic findings is crucial. However, understanding of cytomorphology is imperative in cases where sample is insufficient for cell block material or on-site adequacy evaluation is needed. Also, as demonstrated in all the 3 cases, an adequate clinical history and correlation with radiologic impression are equally important.

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Keywords:

cytology; diagnostic pitfalls; pulmonary pathology; respiratory cytology

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.