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Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied

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Abstract

Optimal histopathological analysis of biopsies from metastases of neuroendocrine tumor (NET) of the lung requires more than morphology only. Additional parameters such as Ki-67 labeling index are required for adequate diagnosis, but few studies have compared reproducibility of different counting protocols and modalities of reporting on biopsies of lung NET. We compared the results of four different manual counting techniques to establish Ki-67 LI. On 47 paired biopsies and surgical specimens from 22 typical carcinoids (TCs), 14 atypical carcinoids (ACs), six large cell neuroendocrine carcinomas (LCNECs), and five small cell carcinomas (SCCs) immunohistochemical staining of Ki-67 antigen was performed. We counted, in regions of highest nuclear staining (HSR), a full ×40-high-power field (diameter = 0.55 mm), 500 or 2000 cells, or 2 mm2 surface area, including the HSR or the entire biopsy fragment(s). Mitoses and necrosis were evaluated in an area of 2 mm2 or the entire biopsy fragment(s). Between the four counting methods, no differences in Ki-67 LI were observed. However, a Ki-67 LI higher than 5% was found in only four cases when in an HSR, 500 cells were counted (18%), five (23%) when in an HSR 2000 cells were counted, four (18%) when 2 mm2 were counted, and one (5%) TC case when the entire biopsy was counted. A 20% cutoff distinguished TC and AC from LCNEC and SCC with 100% specificity and sensitivity, while mitoses and necrosis failed to a large extent. Ki-67 LI in biopsy samples was concordant with that in resection specimens when 2000 cells, 2 mm2, or the entire biopsy fragment(s) were counted. Our results are important for clinical management of patients with metastases of a lung NET.

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Acknowledgements

This work was supported by Novartis Novartis Farma Italia, Milan, Italy. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, which are the responsibilities of the authors only. The paper has been professionally proofread by PRS (Proof-Reading-Service.com Ltd., Devonshire Business Centre, Works Road, Letchworth Garden City, Herts SG6 1GJ, UK).

This work is dedicated to the memory of Carlotta, an extraordinarily lively girl who untimely died of cancer in the prime of life.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Alessandra Fabbri, Mara Cossa, Angelica Sonzogni, Barbara Valeri & Giuseppe Pelosi

  2. Department of Oncology, University of Turin, Turin, Italy

    Mauro Papotti, Luisella Righi & Gaia Gatti

  3. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Patrick Maisonneuve

  4. Division of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Ugo Pastorino

  5. Department of Oncology and Hemato-oncology, Università degli Studi, Milan, Italy

    Giuseppe Pelosi

  6. Dipartimento di Oncologia ed Emato-oncologia, Via Festa del Perdono, 7, I-20122, Milan, Italy

    Giuseppe Pelosi

Authors
  1. Alessandra Fabbri
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  2. Mara Cossa
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  3. Angelica Sonzogni
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  4. Mauro Papotti
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  5. Luisella Righi
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  6. Gaia Gatti
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  7. Patrick Maisonneuve
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  8. Barbara Valeri
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  9. Ugo Pastorino
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  10. Giuseppe Pelosi
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Corresponding author

Correspondence to Giuseppe Pelosi.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics

The study was approved by the independent ethics committee of the National Tumor Institute IRCCS Foundation, Milan, Italy (accession number INT-18/16). All patients gave written consent for diagnosis and research activities when they were admitted to the hospital.

Electronic supplementary material

Supplemental Material A

Antibody panel used in the current study: all immunoreactions were performed using Envision Flex + DAKO (Flex Plus Polymers with horseradish peroxidase and 3–3′-diaminobenzidine), Dako, Glostrup Denmark. (DOCX 44 kb)

Supplemental Material B

Intraclass correlation coefficient analysis between biopsy samples and surgical specimens. (DOCX 77 kb)

Supplemental Material C

Deming regression on the left and Bland-Altman plots on the right for the evaluation of Ki-67 LI on 500 cells, chromogranin A (%), synaptophysin (%) and mitotic count on 2 mm2 on pre-surgical biopsy samples against surgical specimens. (GIF 3 kb)

High Resolution Image (TIFF 4329 kb)

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Fabbri, A., Cossa, M., Sonzogni, A. et al. Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 470, 153–164 (2017). https://doi.org/10.1007/s00428-016-2062-2

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  • DOI: https://doi.org/10.1007/s00428-016-2062-2

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