What Is the Ki-67 Proliferation Index?
The Ki-67 proliferation index is one of the most valuable tools used to assess how fast neuroendocrine cancers (NETs) are growing. It measures the percentage of tumour cells that are actively dividing, giving doctors important information about how aggressive the disease may be. Ki-67 is a nuclear protein which shows the rate at which cells that are dividing.
To measure this, pathologists use a process called immunohistochemistry. A tumour tissue sample is stained with antibodies that bind to the Ki-67 protein, and the proportion of stained (dividing) cells is then counted under a microscope. This percentage reflects the tumour’s proliferation rate.
This measure provides a consistent way to describe how active a NET is, supporting decisions around treatment intensity, monitoring schedules, and prognosis.
NeuroEndocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with NETs and their loved ones. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of NETs, improving patient care, and encouraging research advancements. Patients can engage with NECA’s comprehensive support and information by calling the NET nurse line.
Ki-67 and tumour grading
The World Health Organization (WHO) grading system for neuroendocrine cancers relies heavily on the Ki-67 proliferation index. It forms part of the core criteria used to classify tumours as low, intermediate, or high grade. These grades are used across gastroenteropancreatic NETs (GEP-NETs), lung NETs, and other sites.
NET classification based on Ki-67 percentage
The current WHO guidelines classify NETs according to both Ki-67 percentage and mitotic count (the number of cell divisions seen under the microscope).
- Grade 1 (Low grade): Ki-67 index less than 3%. These tumours grow slowly and are often well-differentiated, meaning the cancer cells still look and behave somewhat like normal cells.
- Grade 2 (Intermediate grade): Ki-67 index between 3% and 20%. These tumours tend to grow moderately and can behave unpredictably, sometimes remaining stable for years and other times progressing more quickly.
- Grade 3 (High grade): Ki-67 index greater than 20%. These NETs are more aggressive and often require systemic treatments such as chemotherapy or peptide receptor radionuclide therapy (PRRT).
Other Factors Pathologists Assess
Pathologists also look at cellular features and patterns of growth to confirm the tumour’s grade. Low-grade NETs tend to form organised clusters of cells, while high-grade tumours may appear disorganised with abnormal nuclei and higher rates of necrosis (dead tissue). Combining histology with the Ki-67 score provides a more accurate overall picture of the disease.
Prognostic significance
The Ki-67 proliferation index is a powerful predictor of patient outcomes in NETs. Numerous studies have shown a clear relationship between a higher Ki-67 percentage and a poorer prognosis.
- Patients with low-grade NETs (Ki-67 below 3%) often do very well over the long term, often living for many years or even decades.
- Intermediate-grade tumours have more variable outcomes, depending on the primary site and responsiveness to treatment.
- High-grade NETs, particularly those with Ki-67 levels above 50%, tend to behave more like carcinomas, grow more quickly, and are more aggressive, which can lead to a poorer prognosis.
In pancreatic and gastrointestinal NETs, for example, Ki-67 strongly correlates with both progression-free survival and overall survival. This helps clinicians counsel patients on expected outcomes and design appropriate treatment pathways.
Predicting recurrence and disease progression
Even after successful treatment, neuroendocrine cancer could recur, sometimes many years later. A high Ki-67 index at diagnosis increases the likelihood of recurrence and faster disease progression. This marker is therefore one of several tools used to guide follow-up schedules. Patients with higher Ki-67 scores may undergo more frequent imaging and biochemical testing to ensure early detection of new disease activity.
Influence on treatment decisions
The Ki-67 index helps doctors determine treatment for neuroendocrine cancers. Along with other factors, it provides insight into tumour aggressiveness and guides patients toward the right treatment pathway.
Guiding surgical planning and systemic therapies
For localised, low-grade NETs, surgery is often curative. However, in higher-grade NETs with elevated Ki-67 values, additional systemic treatments may be recommended even after surgery although there is currently limited research on the benefits.
In cases where surgery is not possible, Ki-67 guides the use of medical therapies. Patients with Grade 1 and 2 NETs often respond well to somatostatin analogues (SSAs) such as octreotide or lanreotide, which help slow tumour growth and control hormone-related symptoms. In contrast, high-grade NETs with a very high Ki-67 index may require chemotherapy regimens similar to those used for small cell carcinomas.
Limitations of the Ki-67 index
While Ki-67 is a valuable tool, it is not without challenges. Its interpretation can vary between laboratories and even among pathologists within the same institution.
Variability in Measurement and Interpretation
Counting Ki-67-positive cells can be subjective. Differences in staining technique, tissue quality, and the area chosen for counting can lead to inconsistent results. To minimise variability, guidelines recommend counting at least 500 to 2,000 tumour cells in the region with the highest staining (“hot spot”) and reporting the exact percentage.
Efforts are ongoing to standardise the method, and some centres now use digital image analysis to make the counting process more objective and reproducible.
Differences across tumour sites and subtypes
Not all NETs behave the same way, even with similar Ki-67 scores. For instance, a pancreatic NET with a Ki-67 of 15% might progress differently from a small-bowel NET with the same index. The underlying biology of the primary site, hormone activity, and molecular mutations can all modify prognosis. Therefore, clinicians interpret Ki-67 within the broader clinical context rather than in isolation.
Future directions
Research into Ki-67 and its relationship to NET prognosis continues to evolve. Scientists are exploring how this marker can be combined with other molecular and clinical factors to create more refined prognostic models.
Integration with other biomarkers
Combining Ki-67 with additional biomarkers such as chromogranin A, circulating tumour DNA, and gene expression signatures could enhance accuracy in predicting outcomes. Machine-learning algorithms are also being developed to integrate these variables and produce risk scores tailored to individual patients.
Recent studies suggest that changes in Ki-67 levels over time, rather than a single measurement at diagnosis, may offer deeper insights into treatment response and disease progression. Tracking Ki-67 dynamically could one day become part of personalised monitoring strategies.
Towards more refined prognostic models
Beyond Ki-67, advances in molecular profiling are identifying new prognostic indicators, such as mutations in MEN1, DAXX, ATRX, and mTOR pathway genes. Integrating genetic data with proliferation indices may improve risk prediction, helping to guide early intervention and clinical trial enrolment.
Artificial intelligence is also beginning to play a role, with automated systems capable of analysing digital pathology slides to measure Ki-67 more precisely and identify subtle features that may correlate with patient outcomes.
What to expect as an NET patient
The Ki-67 proliferation index is one of several important indicators used to assess activity and prognosis in neuroendocrine cancer. It provides vital information about how quickly a tumour is growing, how it may behave, and what treatments are likely to be effective.
By helping clinicians distinguish between indolent and aggressive disease, Ki-67 underpins the grading system that guides all aspects of NET management from surgery and systemic therapies to long-term follow-up and surveillance.
While limitations remain in measurement consistency and tumour-to-tumour variability, ongoing research into combined biomarkers and digital pathology promises to enhance the accuracy and clinical utility of Ki-67. As science progresses, this marker will continue to be an essential part of understanding, treating, and predicting outcomes in Neuroendocrine Cancer.
Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line
Sources
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Ki-67 Proliferation Index in NET Grading.
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Refining NET Grading With Ki-67 Imaging.
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Utility of Ki-67 as a Prognostic Biomarker in Pulmonary Neuroendocrine Tumours.
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https://staging.seer.cancer.gov/eod_public/input/3.2/net_ampulla/ki67/?~net_ampulla~= - College of American Pathologists (CAP).
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https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-guidelines/evaluation-of-gastroenteropancreatic-neuroendocrine-tumors
