title: Is the current diagnostic algorithm reliable for selecting cases for EGFR- and KRAS-mutation analysis in lung cancer?
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pulmonology, Albert Schweitzer Hospital, Dordrecht, The Netherlands. Electronic address: j.vincenten@asz.nl.
authors.forename: Julien P L
authors.initials: JP
authors.lastname: Vincenten
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Grünberg
authors.affiliation: Clatterbridge Cancer Centre, Liverpool Heart & Chest Hospital, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Postmus
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Birgit I
authors.initials: BI
authors.lastname: Witte
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D003951:Diagnostic Errors; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D017410:Practice Guidelines as Topic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; C115051:TP63 protein, human; C504003:TTF1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adenocarcinoma; EGFR-mutation; Immunohistochemistry; KRAS-mutation; Lung cancer; Squamous cell carcinoma; p40; p63