Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens

J Thorac Oncol. 2011 Nov;6(11):1849-56. doi: 10.1097/JTO.0b013e318227142d.


Background: There is growing evidence that lung adenocarcinoma and squamous cell carcinoma (SQCC) have distinct oncogenic mutations and divergent therapeutic responses, which is driving the heightened emphasis on accurate pathologic subtyping of non-small cell lung carcinoma (NSCLC). The relative feasibility and accuracy of NSCLC subtyping by small biopsy versus cytology is not well established, particularly in current practice where immunohistochemistry (IHC) is becoming routinely used to aid in this distinction.

Methods: Concurrent biopsy and cytology specimens obtained during a single procedure and diagnosed as NSCLC during a 2-year period (n = 101) were reviewed. Concordance of diagnoses in the two methods was assessed. Accuracy was determined based on subsequent resection or autopsy diagnosis (n = 21) or IHC for thyroid transcription factor 1 and p63 on a subset of cases (n = 43).

Results: The distribution of definitive versus favored versus unclassified categories (reflecting the degree of diagnostic certainty) was similar for biopsy (71% versus 23% versus 6%, respectively) and cytology (69% versus 19% versus 12%, respectively), p = 0.29. When results from paired specimens were combined, the rate of definitive diagnoses by at least one method was increased to 84% and the unclassified rate was decreased to 4%. NSCLC subtype concordance between biopsy and cytology was 93%. Kappa coefficient (95% confidence interval) for agreement between methods was 0.88 (0.60-0.89) for adenocarcinoma and 0.76 (0.63-0.89) for SQCC. In pairs with discordant diagnoses (n = 7) the correct tumor type was identified with a similar frequency by biopsy (n = 4) and cytology (n = 3). Factors contributing to mistyping were poor differentiation, necrosis, low cellularity, and lack of supporting IHC. All concordant diagnoses for which verification was available (n = 57) were correct. IHC was used more frequently to subtype NSCLC in biopsy than cytology (32% versus 6%; p = 0.0001).

Conclusions: Small biopsy and cytology achieve comparable rates of definitive and accurate NSCLC subtyping, and the optimal results are attained when the two modalities are considered jointly. The lower requirement for IHC in cytology highlights the strength of cytomorphology in NSCLC subtyping. Whenever clinically feasible, obtaining parallel biopsy and cytology specimens is encouraged.

Publication types

  • Comparative Study

MeSH terms

  • Adenocarcinoma / classification
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Biomarkers, Tumor / metabolism*
  • Biopsy, Fine-Needle
  • Bronchi / metabolism
  • Bronchi / pathology
  • Carcinoma, Non-Small-Cell Lung / classification*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Squamous Cell / classification
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cytodiagnosis*
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / classification*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Membrane Proteins / metabolism
  • Neoplasm Staging
  • Nuclear Proteins / metabolism
  • Prognosis
  • Thyroid Nuclear Factor 1
  • Transcription Factors / metabolism


  • Biomarkers, Tumor
  • CKAP4 protein, human
  • Membrane Proteins
  • NKX2-1 protein, human
  • Nuclear Proteins
  • Thyroid Nuclear Factor 1
  • Transcription Factors