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Does histological assessment accurately distinguish separate primary lung adenocarcinomas from intrapulmonary metastases? A study of paired resected lung nodules in 32 patients using a routine next-generation sequencing panel for driver mutations
  1. Frido K Bruehl1,
  2. Erika E Doxtader1,
  3. Yu-Wei Cheng1,
  4. Daniel H Farkas1,
  5. Carol Farver2,
  6. Sanjay Mukhopadhyay1
  1. 1Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA
  2. 2Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Sanjay Mukhopadhyay, Department of Pathology, Cleveland Clinic, Cleveland, USA; mukhops{at}


Aim Various approaches have been reported for distinguishing separate primary lung adenocarcinomas from intrapulmonary metastases in patients with two lung nodules. The aim of this study was to determine whether histological assessment is reliable and accurate in distinguishing separate primary lung adenocarcinomas from intrapulmonary metastases using routine molecular findings as an adjunct.

Methods We studied resected tumour pairs from 32 patients with lung adenocarcinomas in different lobes. In 15 of 32 tumour pairs, next-generation sequencing (NGS) for common driver mutations was performed on both nodules. The remainder of tumour pairs underwent limited NGS, or EGFR genotyping. Tumour pairs with different drivers (or one driver/one wild-type) were classified as molecularly unrelated, while those with identical low-frequency drivers were classified as related. Three pathologists independently and blinded to the molecular results categorised tumour pairs as related or unrelated based on histological assessment.

Results Of 32 pairs, 15 were classified as related by histological assessment, and 17 as unrelated. Of 15 classified as related by histology, 6 were classified as related by molecular analysis, 4 were unrelated and 5 were indeterminate. Of 17 classified as unrelated by histology, 14 were classified as unrelated by molecular analysis, none was related and 3 were indeterminate. Histological assessment of relatedness was inaccurate in 4/32 (12.5%) tumour pairs.

Conclusions A small but significant subset of two-nodule adenocarcinoma pairs is inaccurately judged as related by histological assessment, and can be proven to be unrelated by molecular analysis (driver gene mutations), leading to significant downstaging.

  • lung neoplasms
  • pathology
  • molecular
  • pathology
  • surgical

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  • Handling editor Runjan Chetty.

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  • Contributors Conception and design: FB, EED, SM. Development of methodology: FB, EED, Y-WC, DHF, SM. Acquisition of data: FB, EED, Y-WC, CF, DHF, SM. Analysis and interpretation of data: FB, EED, Y-WC, DHF, SM. Writing, review and/or revision of the manuscript: FB, EED, Y-WC, DHF, CF, SM. Administrative, technical or material support: Y-WC, DHF. Study supervision: EED, SM.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol was approved by our Institutional Review Board (18-1300).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information. Supplemental data files are available.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.