• 60 year old woman with a 2.5 cm solitary pulmonary lesion (Diagn Cytopathol 2024;52:589)
• 70 year old woman with suspected left upper lobe of lung neoplasm and enlarged left hilar lymph node (Diagn Cytopathol 2022;50:172)
• 70 year old man with hemoptysis and bilateral pulmonary infiltrates (Respir Care 2004;49:186)

Reactive causes for an atypical appearance of respiratory cells

• Treatment effect from radiation or chemotherapy (Diagn Cytopathol 1988;4:9, Pathologica 1991;83:317)
  • Clinical history is beneficial for this diagnosis
  • Nuclei
    • Nuclear irregularity, cytomegaly, often low N:C ratio
    • Large nucleoli
    • Smudgy chromatin pattern
  • Cytoplasm
    • Abundant cytoplasm
    • Cytoplasmic vacuolization
• Infective, inflammatory or alveolar damage (Indian J Chest Dis Allied Sci 2008;50:33, Acta Cytol 2000;44:640, Diagn Cytopathol 2022;50:E107, Diagn Cytopathol 2014;42:993)
  • Useful to maintain a high index of suspicion in the appropriate clinical setting
  • Nuclei
    • Nuclear enlargement or hyperchromasia
    • Nuclear crowding / overlap
    • Prominent nucleoli
  • Background acute inflammation, debris, extracellular material
  • Necrotizing granulomas
• Squamous metaplasia (Diagn Cytopathol 2011;39:144, Arch Pathol Lab Med 2007;131:1700)
  • Oval to round squamous cells
  • Hyperchromatic nuclei
  • With or without orangeophilic cytoplasm
  • Variable N:C ratio (often low)
  • With or without background debris
  • Can mimic squamous cell carcinoma

Mimickers of adenocarcinoma

• Goblet cell metaplasia (Acta Cytol 2022;66:532)
  • Cohesive group of cells
  • Intracytoplasmic mucin
  • Lack of nuclear membrane irregularities
  • Can mimic mucinous adenocarcinoma
• Reserve cell hyperplasia (Acta Cytol 2022;66:532)
  • Cohesive cellular arrangement
  • Hyperchromasia
  • Increased N:C ratio
  • Periphery with ciliated cells
  • Often seen in bronchial brushing / washing specimens
• Pulmonary macrophages (Trends Mol Med 2016;22:303)
  • Round to oval cells
  • Moderate and vacuolated cytoplasm
  • Round, elongated or indented nucleus
  • With or without pigmented inclusions (anthracotic or hemosiderin laden); finer than melanin pigment
• Hyperplastic and reactive pneumocytes (Arch Pathol Lab Med 2020;144:443)
  • Single or in clustered arrangements
  • Nuclear enlargement, with or without contour irregularity
  • Prominent nucleoli
  • Vesicular chromatin
  • Variably dense to vacuolated cytoplasm
  • Can mimic carcinoma due to nuclear atypia

Other

• Spindle cell lesions (Ann Diagn Pathol 2001;5:216)
  • Ancillary testing is important for final categorization
  • Differential diagnosis is broad and ranges from benign to malignant
  • Correlate with clinicoradiographic impressions

Contributed by Juanita E. Ferreira, M.D.


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Which of the following is most likely to warrant an atypical category designation when reporting respiratory cytology specimens?

1. Abundant neutrophilic inflammation
2. Lymphocytic proliferation
3. Pulmonary macrophages
4. Reactive changes after radiation therapy
5. Unremarkable bronchiolar epithelial cells

D. Reactive changes after radiation therapy. Postradiation therapy, respiratory cells can develop abnormal features that mimic malignancy such as enlarged nuclei with irregularity and prominent nucleoli. However, these cells often have other reassuring morphologic features such as a low N:C ratio, smudgy chromatin pattern and cytoplasmic vacuolization. Overall, these cases are best put in the atypical category, especially if there is a lack of clinical history of radiation therapy. Answers C and E are incorrect because they are typically found in benign respiratory samples. Answers A and B are incorrect because the atypical category is reserved for cases that suggest potential malignancy but lack the quantity or definitive features required to confirm a malignant or benign diagnosis.

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Reference: Lung - Atypical

Which of the following is a highly recommended first step to take before categorizing the cytologic respiratory specimen shown above as atypical?

1. Assessment by flow cytometry
2. Correlation of clinical and radiographic findings
3. Performing special stains for infectious organisms
4. Perform molecular testing
5. Repeat sampling

B. Correlation of clinical and radiographic findings. Clinical and radiographic findings should be reviewed before categorizing a specimen as atypical. This ensures that cytologic features are interpreted in the right clinical and radiographic context. Other testing can then be performed if warranted. Answer A is incorrect because while flow cytometry can provide information about cellular populations, it is not the first step in determining whether a specimen is atypical. Answer C is incorrect because the cytologic features should be correlated with clinical and radiographic findings prior to ordering special stains to determine whether an infection is a likely consideration. Answer D is incorrect because It is not the first step in categorizing a specimen as atypical, as molecular testing is specific to certain genetic alterations. Answer E is incorrect because repeat sampling is only necessary when the initial specimen is inadequate or nondiagnostic; therefore, the current specimen should be assessed first in the context of clinical and radiographic findings.

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Reference: Lung - Atypical