Is the current diagnostic algorithm reliable for selecting cases for EGFR- and KRAS-mutation analysis in lung cancer?

Lung Cancer. 2015 Jul;89(1):19-26. doi: 10.1016/j.lungcan.2015.04.005. Epub 2015 Apr 20.

Abstract

Objectives: Adenocarcinoma (ADC) of the lung may harbor EGFR- or KRAS-mutations, which are relevant for treatment decisions. There is no consensus on the percentages of EGFR- and KRAS-mutations that are allowed to be missed by a diagnostic algorithm, although a percentage of less than 1% for EGFR-mutations has been suggested. The current guidelines do not advise to perform EGFR-mutation analysis in unequivocal squamous cell carcinoma (SqCC). For KRAS-mutations no threshold for missing cases is suggested yet. To improve segregation between ADC and SqCC in small samples, the classification of lung cancer was updated in 2011, adding immunohistochemistry (IHC) for p63 and TTF-1 to the diagnostic algorithm. In this study we examined how many cases with an EGFR- or KRAS-mutation in our database would have been missed, if the current guideline for selecting cases for mutation analysis would have been applied.

Materials and methods: From an institutional lung cancer database of specimens analyzed for EGFR- and KRAS-mutations (n=816), cases harboring a mutation without being treated prior with an EGFR-TKI were selected (n=336). Corresponding original histological diagnoses and IHC for TTF-1, p63 and PAS-D were collected. Cases with SqCC on HE or with an IHC pattern favoring SqCC were reassessed according to the criteria of the 2011-classification.

Results: From the 336 cases 70% had a KRAS-mutation and 30% an EGFR-mutation. The number of cases with SqCC on HE and/or an IHC-profile favoring SqCC was 12. After the reassessment six specimens (1.8%) would not have been tested for EGFR-/KRAS-mutations, if the current diagnostic algorithm had been used: 2.0% of EGFR-mutations and 1.7% KRAS-mutations. All six cases were NSCLC with an IHC-profile favoring SqCC.

Conclusion: Most NSCLC-cases with EGFR- and KRAS-mutations are selected by the current diagnostic algorithm. As a small but relevant fraction is missed, there is room for improvement.

Keywords: Adenocarcinoma; EGFR-mutation; Immunohistochemistry; KRAS-mutation; Lung cancer; Squamous cell carcinoma; p40; p63.

MeSH terms

  • Adenocarcinoma / chemistry
  • Adenocarcinoma / diagnosis*
  • Adenocarcinoma / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms*
  • Carcinoma, Squamous Cell / chemistry
  • Carcinoma, Squamous Cell / diagnosis*
  • Carcinoma, Squamous Cell / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / analysis
  • Diagnostic Errors
  • ErbB Receptors / genetics*
  • Female
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / chemistry
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Mutation*
  • Patient Selection
  • Practice Guidelines as Topic
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Transcription Factors / analysis
  • Tumor Suppressor Proteins / analysis
  • Young Adult

Substances

  • DNA-Binding Proteins
  • KRAS protein, human
  • TP63 protein, human
  • TTF1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)