Proliferative index: Difference between revisions

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{{short description|Index measuring the progression of cancer}}

Proliferation, as one of the [[Hallmarks of cancer|hallmarks]] and most fundamental biological processes in tumors,<ref>{{Cite journal|lastlast1=Hanahan|firstfirst1=Douglas|last2=Weinberg|first2=Robert A.|title=Hallmarks of Cancer: The Next Generation|url=http://linkinghub.elsevier.com/retrieve/pii/S0092867411001279|journal=Cell|volume=144|issue=5|pages=646–674|doi=10.1016/j.cell.2011.02.013|pmid=21376230|year=2011|doi-access=free}}</ref>, is associated with tumor progression, response to therapy, and cancer patient survival.<ref>{{Cite journal|lastlast1=Yerushalmi|firstfirst1=Rinat|last2=Woods|first2=Ryan|last3=Ravdin|first3=Peter M|last4=Hayes|first4=Malcolm M|last5=Gelmon|first5=Karen A|title=Ki67 in breast cancer: prognostic and predictive potential|url=http://linkinghub.elsevier.com/retrieve/pii/S1470204509702621|journal=The Lancet Oncology|volume=11|issue=2|pages=174–183|doi=10.1016/s1470-2045(09)70262-1|pmid=20152769|date=February 2010}}</ref>. Consequently, the evaluation of a tumor '''proliferative index''' (or growth fraction) has clinical significance in characterizing many solid tumors and hematologic malignancies.<ref>{{Cite journal|lastlast1=Loo|firstfirst1=Suet Kee|last2=Ch'ng|first2=Ewe Seng|last3=Lawrie|first3=Charles H.|last4=Muruzabal|first4=María Arestin|last5=Gaafar|first5=Ayman|last6=Pomposo|first6=María Puente|last7=Husin|first7=Azlan|last8=Salleh|first8=Md. Salzihan Md.|last9=Banham|first9=Alison H.|title=DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas|url=http://linkinghub.elsevier.com/retrieve/pii/S0031302517302106|journal=Pathology|volume=49|issue=7|pages=731–739|doi=10.1016/j.pathol.2017.08.009|pmid=29074044|date=December 2017|url=https://ora.ox.ac.uk/objects/uuid:f5b74a28-1c4d-45f8-9d2f-64cb670d8fc8}}</ref>. This has led investigators to develop different technologies to evaluate the proliferation index in tumor samples. The most commonly used methods in evaluating a proliferative index include [[Mitoticmitotic index|mitotic indexing]]ing, [[thymidine]]-labeling index, [[bromodeoxyuridine]] assay, the determination of fraction of cells in various phases of cell cycle, and the [[Immunohistochemistry|immunohistochemical]] evaluation of cell cycle-associated proteins.

== Mitotic index (also called mitotic count) ==

[[File:Mitosis in a neuroendocrine tumor.jpg|thumb|Mitosis in a [[neuroendocrine tumor]].]]

Mitotic indexing is the oldest method of assessing proliferation and is determined by counting the number of mitotic figures (cells undergoing mitosis) through a light microscope on [[H&E stain|H&E]] stained sections. It is usually expressed as the number of cells per microscopic field. Cells in the mitotic phase are identified by the typical appearance of their chromosomes in the cell during the mitotic phase of the cell cycle.<ref>{{Cite journal|last=Baak|first=J. P.|date=July 1990|title=Mitosis counting in tumors|url=https://www.ncbi.nlm.nih.gov/pubmed/2131787|journal=Human Pathology|volume=21|issue=7|pages=683–685|issn=0046-8177|pmid=2131787|doi=10.1016/0046-8177(90)90026-2}}</ref>. Usually the number of mitotic figures is expressed as the total number in a defined number of high power fields, such as 10 mitoses in 10 high power fields. Since the field of vision area can vary considerably between different microscopes, the exact area of the high power fields should be defined in order to compare results from different studies. Accordingly, one of the main problems of counting mitosis has been the reproducibility. Thus, the need for standardized methodology and strict protocols is important to achieve reproducible results.<ref>{{Cite journal|lastlast1=van Diest|firstfirst1=P. J.|last2=Baak|first2=J. P.|last3=Matze-Cok|first3=P.|last4=Wisse-Brekelmans|first4=E. C.|last5=van Galen|first5=C. M.|last6=Kurver|first6=P. H.|last7=Bellot|first7=S. M.|last8=Fijnheer|first8=J.|last9=van Gorp|first9=L. H.|date=June 1992|title=Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project|url=https://www.ncbi.nlm.nih.gov/pubmed/1592381|journal=Human Pathology|volume=23|issue=6|pages=603–607|issn=0046-8177|pmid=1592381|doi=10.1016/0046-8177(92)90313-r}}</ref> Automated image analysis using deep learning-based algorithms has been proposed as a promising tool to assist pathologists and thereby improve reproducibility and accuracy.<ref>{{cite journal |last1=Bertram |first1=Christof A |last2=Aubreville |first2=Marc |last3=Donovan |first3=Taryn A |last4=Bartel |first4=Alexander |last5=Wilm |first5=Frauke |last6=Marzahl |first6=Christian |last7=Assenmacher |first7=Charles-Antoine |last8=Becker |first8=Kathrin |last9=Bennett |first9=Mark |last10=Corner |first10=Sarah |last11=Cossic |first11=Brieuc |last12=Denk |first12=Daniela |last13=Dettwiler |first13=Martina |last14=Gonzalez |first14=Beatriz Garcia |last15=Gurtner |first15=Corinne |last16=Haverkamp |first16=Ann-Kathrin |last17=Heier |first17=Annabelle |last18=Lehmbecker |first18=Annika |last19=Merz |first19=Sophie |last20=Noland |first20=Erika L |last21=Plog |first21=Stephanie |last22=Schmidt |first22=Anja |last23=Sebastian |first23=Franziska |last24=Sledge |first24=Dodd G |last25=Smedley |first25=Rebecca C |last26=Tecilla |first26=Marco |last27=Thaiwong |first27=Tuddow |last28=Fuchs-Baumgartinger |first28=Andrea |last29=Meuten |first29=Donald J |last30=Breininger |first30=Katharina |last31=Kiupel |first31=Matti |last32=Maier |first32=Andreas |last33=Klopfleisch |first33=Robert |title=Computer-assisted mitotic count using a deep learning–based algorithm improves interobserver reproducibility and accuracy |journal=Veterinary Pathology |year=2021 |volume=59 |issue=2 |pages=211–226 |doi=10.1177/03009858211067478 |pmid=34965805 |s2cid=245567911 |doi-access=free |pmc=8928234 }}</ref>

== Thymidine-labeling index ==

Thymidine-labeling indexing is determined by counting the number of tumor nuclei labeled on [[Autoradiograph|autoradiographedautoradiograph]]ed sections after incubating the tumor cells with thymidine. Rapidly proliferating cells readily update more [[radiolabeled]] Thymidine, which produces darker spots on the autoradiograph film.<ref>{{Cite journal|last=Silvestrini|first=R.|date=1994-10-01|title=Cell kinetics: prognostic and therapeutic implications in human tumours|url=https://doi.org/10.1111/j.1365-2184.1994.tb01376.x|journal=Cell Proliferation|language=en|volume=27|issue=10|pages=579–596|doi=10.1111/j.1365-2184.1994.tb01376.x|s2cid=84639747|issn=1365-2184}}</ref>.

== Bromodeoxyuridine assay: ==

A bromodeoxyuridine assay, similar to thymidine-labeling indexing, incubates cells with radiolabeled bromodeoxyuridine, which is taken up at a greater rate by proliferating cells, and then uses a film to image the distribution of radiolabeled bromodeoxyuridine in cells.

== S-phase fraction evaluation: ==

Evaluating DNA [[Histogram|histogramshistogram]]s through flow cytometry provides an estimate of the fractions of cells within each of the phases in the cell cycle. Cell nuclei are stained with a DNA binding stain and the amount of staining is measured from the histogram.<ref>{{Cite journal|lastlast1=Wenger|firstfirst1=C. R.|last2=Beardslee|first2=S.|last3=Owens|first3=M. A.|last4=Pounds|first4=G.|last5=Oldaker|first5=T.|last6=Vendely|first6=P.|last7=Pandian|first7=M. R.|last8=Harrington|first8=D.|last9=Clark|first9=G. M.|date=October 1993|title=DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients|url=https://www.ncbi.nlm.nih.gov/pubmed/8123871|journal=Breast Cancer Research and Treatment|volume=28|issue=1|pages=9–20|issn=0167-6806|pmid=8123871|doi=10.1007/BF00666351|s2cid=12798221}}</ref>. The fractions of cells within the different cell cycle phases (G0/G1, S and G2/M compartments) can then be calculated from the histogram by computerized cell cycle analysis.

== Immunohistochemical evaluation: ==

The immunohistochemical detection of proliferation related proteins such as [[Ki-67 (protein)|Ki-67]] and proliferating cell nuclear antigen is a commonly used method to determine the proliferation index. Ki-67 is a nuclear antigen expressed in proliferating cells that is coded by the MKI67 gene on chromosome 10, and is expressed during the GI, S, G2, and M phases of the cell cycle. Cells are then stained with a Ki-67 antibody, and the number of stained nuclei is then expressed as a percentage of total tumor cells. It is recommended to count at least 500 tumor cells in the highest labeled area. The Ki-67 score closely correlates with other proliferation markers, and has been shown to have prognostic and predictive value for many different tumor types.<ref>{{Cite journal|lastlast1=de Azambuja|firstfirst1=E|last2=Cardoso|first2=F|last3=Castro|first3=G de|last4=Colozza|first4=M|last5=Mano|first5=M S|last6=Durbecq|first6=V|last7=Sotiriou|first7=C|last8=Larsimont|first8=D|last9=Piccart-Gebhart|first9=M J|date=May 2007|title=Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 15512 155 patients|url=http://www.nature.com/articles/6603756|journal=British Journal of Cancer|language=En|volume=96|issue=10|pages=1504–1513|doi=10.1038/sj.bjc.6603756|pmid=17453008|issn=1532-1827|pmc=2359936}}</ref>. Similarly, [[proliferating cell nuclear antigen]] (PCNA) is a protein associated with cell proliferation that is upregulated in proliferating cells, making it another useful antigen for immunostaining.<ref>{{Cite journal|lastlast1=Wang|firstfirst1=Xing|last2=Wang|first2=Dong|last3=Yuan|first3=Na|last4=Liu|first4=Fanxiao|last5=Wang|first5=Fu|last6=Wang|first6=Bomin|last7=Zhou|first7=Dongsheng|date=2017-10-01|title=The prognostic value of PCNA expression in patients with osteosarcoma|url=http://Insights.ovid.com/crossref?an=00005792-201710130-00023|journal=Medicine|language=ENGLISH|volume=96|issue=41|pages=e8254|doi=10.1097/md.0000000000008254|pmid=29019895|pmc=5662318|issn=0025-7974}}</ref>. It is associated with [[DNA polymerase|DNA polymerase alpha]], which is expressed throughout the phases of the cell cycle. The expression of PCNA also correlates well with other proliferation markers such as mitotic count, S-phase fraction and Ki-67 staining.

== Diagnostic role of proliferation index: ==

The various methods of characterizing the proliferation index have found roles in both the diagnostic and prognostic evaluation of tumors. For instances, the number of mitotic cells is used to classify tumors. In general, a high proliferation index suggests malignancy and [[Grading (tumors)|high-grade tumors]].<ref>{{Cite journal|lastlast1=Elston|firstfirst1=C. W.|last2=Ellis|first2=I. O.|date=November 1991|title=Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up|url=https://www.ncbi.nlm.nih.gov/pubmed/1757079|journal=Histopathology|volume=19|issue=5|pages=403–410|issn=0309-0167|pmid=1757079|doi=10.1111/j.1365-2559.1991.tb00229.x|s2cid=17622089}}</ref>. Among solid tumors, the clinical significance of the proliferation index on breast cancer has been extensively studied. Mitotic counting has also been shown in multiple studies to have prognostic value in breast cancer, where a lower count of mitotic cells correlates with a more favorable outcome, and thus has been incorporated into part of the histological grading system. The Ki-67 labelling index has also been found to have prognostic significance where in many clinical practice guidelines, evaluation of Ki-67 in newly diagnosed invasive breast carcinomas is recommended.<ref>{{Cite journal|lastlast1=Dowsett|firstfirst1=Mitch|last2=Nielsen|first2=Torsten O.|last3=A’Hern|first3=Roger|last4=Bartlett|first4=John|last5=Coombes|first5=R. Charles|last6=Cuzick|first6=Jack|last7=Ellis|first7=Matthew|last8=Henry|first8=N. Lynn|last9=Hugh|first9=Judith C.|date=2011-11-16|title=Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group|url=https://academic.oup.com/jnci/article/103/22/1656/890097|journal=JNCI: Journal of the National Cancer Institute|language=en|volume=103|issue=22|pages=1656–1664|doi=10.1093/jnci/djr393|pmid=21960707|issn=0027-8874|pmc=3216967}}</ref>. Additionally, the tumor proliferation index has been used to predict the response to systemic chemotherapies in patients who are receiving [[Neoadjuvant therapy|neoadjuvant]] systemic therapy where patients who have tumors with high tumor proliferative index respond better to systemic cytotoxic therapies than those who have tumors with a low tumor proliferative index.<ref>{{Cite journal|lastlast1=Groheux|firstfirst1=David|last2=Biard|first2=L.|last3=Lehmann-Che|first3=J.|last4=Teixeira|first4=L.|last5=Bouhidel|first5=F. A.|last6=Poirot|first6=B.|last7=Bertheau|first7=P.|last8=Merlet|first8=P.|last9=Espié|first9=M.|date=2018-04-04|title=Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer|url=https://link.springer.com/article/10.1007/s00259-018-3998-z|journal=European Journal of Nuclear Medicine and Molecular Imaging|volume=45|issue=8|language=en|pages=1–101279–1288|doi=10.1007/s00259-018-3998-z|pmid=29616304|s2cid=4570270|issn=1619-7070}}</ref>.

==References==

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[[Category:Growth factors]]

[[Category:Oncology]]

{{Oncology-stub}}