The Ki-67 protein is a marker widely used in oncology to assess the proliferation rate of tumor cells. This assessment is performed using immunohistochemistry (IHC), which makes the protein visible under a microscope. The resulting Ki-67 score, reported as a percentage, provides information about how aggressively a tumor is growing. Understanding this percentage helps determine the biological nature of a cancer and guides subsequent treatment decisions.
Ki-67 as a Marker of Cell Proliferation
The Ki-67 protein is a large, non-histone nuclear protein directly linked to cell division. It is expressed exclusively during the active phases of the cell cycle: G1, S, G2, and M (mitosis). When a cell is in its resting state (G0 phase), the Ki-67 protein is absent or rapidly degraded. Consequently, its detection acts as a reliable indicator of the fraction of cells within a tissue that are actively preparing to divide.
Ki-67 also has structural roles within the cell nucleus. During interphase, it helps organize heterochromatin, the tightly packed form of DNA. As the cell enters mitosis, the protein relocates to coat the condensed chromosomes, forming the perichromosomal layer. The concentration of Ki-67 in a tumor mass serves as a measure for the overall growth fraction of the cancer.
How Immunohistochemistry Works
Immunohistochemistry is the laboratory method used to visualize the Ki-67 protein within a tissue sample, typically obtained via a biopsy. The process begins with fixing the tissue, usually in formalin, and embedding it in a paraffin wax block. Thin sections of this tissue are then placed onto glass slides, ready for staining.
The technique involves applying a specific primary antibody designed to bind only to the Ki-67 protein within the cell nucleus. A secondary antibody is then introduced, which binds to the first antibody and is linked to an enzyme. A chemical substrate (chromogen) is added, reacting with the enzyme to produce a visible color, typically a localized brown stain. The final percentage score is derived by counting the proportion of these stained nuclei relative to the total number of tumor cell nuclei viewed under a microscope.
Standardizing the Ki-67 Scoring Process
Generating a reliable Ki-67 score presents analytical challenges due to variability in both the tumor tissue and the interpretation process. Tumors often exhibit “hotspots,” which are small regions with a significantly higher density of proliferating cells. This spatial variation requires pathologists to perform a “global assessment,” counting cells across multiple fields to ensure the final score accurately represents the tumor’s entire proliferation rate.
The visual counting method can introduce subjectivity, leading to differences in scoring between pathologists (inter-observer variability). To mitigate this, international groups have established guidelines for standardization. These recommendations include counting a minimum of 500 to 2,000 tumor cells and adhering to strict protocols for pre-analytical steps, such as tissue fixation time.
Interpreting Ki-67 Results in Cancer Treatment
The Ki-67 percentage is widely used as both a prognostic and predictive biomarker, particularly in breast cancer management. As a prognostic marker, the score helps estimate the likelihood of disease recurrence or the patient’s long-term outcome. A low score suggests a slow growth rate and a favorable prognosis, while a high score indicates a more aggressive tumor with a higher risk of recurrence.
The score’s predictive utility forecasts the tumor’s likely response to specific systemic treatments. Tumors with a low Ki-67 index (often less than 14% to 20%) are classified as Luminal A-like, suggesting high responsiveness to endocrine (hormone) therapy alone. These patients are often spared the toxic side effects associated with chemotherapy.
Conversely, a high Ki-67 score (typically above 20% to 30%) places the tumor into a more proliferative category, such as Luminal B-like. This elevated score suggests the tumor is less dependent on hormone signaling for growth and is more likely to benefit from the addition of chemotherapy. High Ki-67 scores also identify patients who may benefit from targeted therapies, such as CDK4/6 inhibitors.
The clinical utility of the score is strongest at the extremes, where very low scores (e.g., 5% or less) and very high scores (e.g., 30% or more) provide clear guidance. The intermediate range often remains a source of discussion, requiring oncologists to integrate the Ki-67 result with other factors. These factors include tumor size, lymph node status, and tumor grade to finalize the optimal treatment strategy.