Stains & molecular markers
Ki67 / MIB1
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: (Ki67[title] OR MIBI[title]) stain
Ki67 / MIB1
Author: Monika Roychowdhury, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Topic Completed: 1 March 2018
Minor changes: 17 December 2020
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: (Ki67[title] OR MIBI[title]) stain
Table of Contents
Definition / general | Essential features | Prognostic factors | Uses by pathologists | Microscopic (histologic) description | Microscopic (histologic) images | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Roychowdhury M. Ki67. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainski67.html. Accessed January 25th, 2021.
Definition / general
- Marker of cell proliferation first described in 1983 (Int J Cancer 1983;31:13)
- Name derived from Kiel, Germany (city of origin) and the clone number in the 96 well plate (Wikipedia)
- Labile, nonhistone nuclear protein expressed in G1, S, G2 and M phases of cell cycle, then rapidly catabolized at end of M phase and not detectable in G0 and early G1 cells (J Cell Physiol 2000;182:311)
- MIB1 is the IgG1 antibody against Ki67 for formalin fixed, paraffin embedded tissue
Essential features
- Marker of cell proliferation
- Nuclear stain
- Considered a prognostic factor of breast cancer
- Included in Oncotype DX® (21 prospectively selected genes to predict risk of recurrence and chemotherapy benefit in node negative, ER+ women)
Prognostic factors
- Used for prognosis of relative responsiveness, resistance to chemotherapy or endocrine therapy and biomarker of treatment efficacy (high percentage reflects worse prognosis)
- High Ki67 predicts higher recurrence and progression in nonmuscle invasive bladder cancer than those with low Ki67 expression (Oncotarget 2017;8:100614)
- Superficial noninvasive papillary urothelial neoplasms of bladder show higher grade and recurrence with high Ki67 expression(Rev Col Bras Cir 2012;39:394)
- Chordoma: matrix poor phenotype and higher rate of metastasis associated with high Ki67 expression; also, increase in progression associated with higher Ki67 (Eur Spine J 2016;25:4016)
- Prostate cancer: High Ki67 associated with higher Gleason grade and worse prognosis (Br J Cancer 2013;108:271, Urol Ann 2015;7:488)
Uses by pathologists
- Nuclear stain; cytoplasmic staining is disregarded
- Distinguish benign / nonneoplastic and malignant / neoplastic lesions:
- Anus / cervix: HSIL (Ki67+) versus atrophy or normal (Ki67-, Am J Surg Pathol 2010;34:1449)
- Colonic polyp with cautery artifact: distinguish adenoma (Ki67+) from nonadenomatous polyp (Ki67-, Arch Pathol Lab Med 2007;131:1089)
- Lymph node, sentinel node biopsy: distinguish melanoma (Ki67+) from nevus cells (Ki67-, Am J Surg Pathol 2002;26:1351)
- Uterus: clear cell carcinoma (Ki67+) versus Arias-Stella reaction (Ki67-)
- Placenta: distinguish hyperplasia of intermediate trophoblast (Ki67+) from exaggerated placental site (Ki67-)
- Adrenocortical tumors: distinguish benign and malignant (Am J Surg Pathol 2002;26:1612)
- Grading:
- Invasive breast carcinoma: component of grading in addition to tubule formation and nuclear pleomorphism
- Breast phyllodes tumor: distinguish benign, borderline, malignant (low grade / high grade, Mod Pathol 2001;14:185)
- Classify / grade neuroendocrine tumors
- Sarcoma: component of grading in addition to necrosis and differentiation
- Part of staging for appendiceal carcinoid and grading for GI neuroendocrine tumors (Hum Pathol 2012;43:489)
- Poor prognostic factor (high levels) in many tumors:
- Bladder papillary urothelial neoplasm of low malignant potential (Cancer 2002;95:784)
- Chordoma (Arch Pathol Lab Med 2010;134:1170)
Microscopic (histologic) description
- Percentage of nuclei with positive staining in tumor cells are scored
- < 10%: low
- 10 - 20%: borderline
- > 20%: high (some variability in current literature regarding cut offs but > 20% is unanimaously considered high)
- Used in surrogate immunohistochemical classification for gene-expression profile based intrinsic breast cancer subtypes (low: luminal A; high: luminal B; higher: HER2; highest: basal-like) ( Hoda: Rosen's Diagnosis of Breast Pathology by Needle Core Biopsy, 4th Edition, 2017)
- May assist in distinguishing benign from malignant breast phyllodes tumor; may correlate with tumor grade and adverse prognosis in malignant phyllodes tumor (Mod Pathol 2001;14:185, Breast J 2002;8:38, Arch Pathol Lab Med 2006;130:1516)
- Grading for neuroendocrine tumors of tubular Gastrointestinal tract and pancreas: low
grade < 3%; intermediate grade 3 - 20%; high grade > 20%)
- Please note that there is a small subgroup of well differentiated neuroendocrine tumors that show > 20% Ki67 and are thus categorized as grade 3
- These tumors show prognosis intermediated between conventional grade 2 and grade 3 and are less chemosensitive than conventional grade 3 tumors ( Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017, Amin: AJCC Cancer Staging Manual, 8th Edition, 2018)
- Useful in histological grading of soft tissue sarcomas (World J Surg Oncol 2016;14:110)
- Useful in grading of meningiomas (J Clin Diagn Res 2016;10:EC15) and predicting risk of recurrence (Cureus 2017;9:e1820)
Microscopic (histologic) images
Contributed by Monika Roychowdhury, M.D., Kaveh Naemi, D.O., Cases #238, #237, #202, #194, AFIP images and Leica Microsystems
Invasive ductal carcinoma breast
Invasive ductal carcinoma (Ki67)
Cervix low grade squamous dysplasia
Cervix high grade squamous dysplasia
Lung typical carcinoid
Lung small cell carcinoma
Stomach well differentiated neuroendocrine tumor
Brain diffuse large B cell lymphoma
Lymph node, Burkitt lymphoma
Skin, symplastic glomus tumor, toe
Small bowel, malignant GIST
Cervix, adenocarcinoma in situ, endocervix
Urethra, clear cell adenocarcinoma
Lymph node, normal
Tonsil, normal
Images hosted on other servers:
Breast, invasive carcinoma, basal-like subtype with high Ki67 index
Breast cancer: luminal A type
Kidney, malignant solitary fibrous tumor
Uterus (left to right), mid proliferative endometrium, day 17 endometrium
Additional references
Board review style question #1
54 year old woman recently received the diagnosis of invasive ductal carcinoma for a right breast mass. Which of the prognostic markers below, if positive, suggest(s) aggressive behavior of the tumor?
- ER
- Ki67
- PR
- p63
Board review style answer #1
