Prognostic Significance of Tumour Grade in NETs

When someone receives a diagnosis of a neuroendocrine cancer (NET), one of the key factors influencing their prognosis is tumour grade. Grade provides important information about how aggressively a tumour is likely to behave and is a central element in treatment planning and long-term monitoring. While every NET is unique, understanding grading gives patients and clinicians a framework to guide decisions and anticipate possible outcomes.

Let’s explore what tumour grading means in the context of NETs, how it is determined, and why it plays such a crucial role in prognosis and care.

NeuroEndocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with NETs, and their families. 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 diagnosed with NETs, can engage with NECA’s comprehensive support and information by calling the NET nurse line.

Understanding tumour grading

Tumour grading is a system used by pathologists to describe how abnormal cancer cells look under the microscope and how quickly they are dividing. In neuroendocrine cancer, grading combines two main pieces of information: cell differentiation and cell proliferation.

• Differentiation refers to how similar tumour cells appear compared to normal neuroendocrine cells. Well-differentiated tumours retain features of normal cells and generally behave less aggressively. Poorly differentiated tumours lose these features, tend to grow faster, and are more likely to spread.
• Proliferation is a measure of how quickly the cells are dividing and multiplying. This is assessed using two markers: the Ki-67 index and the mitotic count.

Together, these factors form the basis of the grading system most widely used today.

The Ki-67 index and mitotic count

The Ki-67 index is a percentage that indicates how many tumour cells are actively dividing. It is measured through immunohistochemistry, where tumour tissue is stained to detect the Ki-67 protein present in dividing cells. Pathologists then count the proportion of cells showing positive staining.

• Low Ki-67 (≤2%): Indicates slow-growing, low-grade tumours.
• Intermediate Ki-67 (3–20%): Suggests moderately aggressive behaviour.
• High Ki-67 (>20%): Associated with rapid proliferation and poor prognosis.

Mitotic count

The mitotic count measures how many cells are undergoing mitosis (cell division) in a defined area of tumour tissue, usually expressed as mitoses per 2 mm². A higher mitotic count correlates with more aggressive disease.

Using both together

Because NETs are heterogeneous, pathologists often rely on both the Ki-67 index and mitotic count to determine the grade. Sometimes, one measure may be higher than the other. In such cases, the higher grade usually takes precedence, ensuring that tumours are not underestimated.

Differences between low, intermediate, and high-grade NETs

The World Health Organization (WHO) grading system for NETs uses the Ki-67 index and mitotic count to classify tumours into three grades:

• Grade 1 (low grade): Well-differentiated, Ki-67 ≤2%, mitotic count <2 per 2 mm². These tumours tend to grow slowly, may remain stable for years, and generally have favourable long-term outcomes.
• Grade 2 (intermediate grade): Well-differentiated, Ki-67 between 3–20%, mitotic count 2–20 per 2 mm². These tumours have a variable clinical course. Some behave indolently, while others progress more rapidly.
• Grade 3 (high grade): Ki-67 >20% or mitotic count >20 per 2 mm². Within grade 3, there are two distinct groups: well-differentiated NETs with high proliferation, and poorly differentiated neuroendocrine carcinomas (NECs). NECs, including small-cell and large-cell subtypes, are highly aggressive and often require systemic chemotherapy.

Impact of grade on prognosis

Tumour grade is one of the most powerful predictors of survival in neuroendocrine cancers. Numerous studies have shown that people with low-grade NETs often live many years after diagnosis, even with metastatic disease, while those with high-grade tumours face much shorter survival times.

Higher-grade tumours could recur after surgery and other forms of treatment and could spread to distant organs. Regular follow-up and imaging are especially important for grade 2 and 3 tumours, as early detection of progression can open up treatment options that may improve outcomes.

Treatment implications of grading

Treatment strategies for NETs are closely tied to tumour grade.

Well-differentiated, low to intermediate-grade NETs

• Surgery is often the primary treatment when tumours are localised.
• Somatostatin analogues (SSAs) may be used to control symptoms and slow tumour growth in functioning and non-functioning NETs.
• Peptide receptor radionuclide therapy (PRRT) is effective for many grade 1 and 2 NETs with somatostatin receptor expression.
• Targeted therapies such as everolimus and sunitinib are more common in pancreatic NETs.

High-grade NETs and NECs

• Chemotherapy is the mainstay, particularly platinum-based regimens, due to the aggressive nature of these tumours.
• Surgery may be considered in selected cases, but systemic therapy is often prioritised.
• Clinical trials may offer access to novel therapies, including immunotherapy combinations.

Tailoring management

By accurately grading tumours, clinicians can tailor treatments to balance efficacy with side effects. For example, a person with a grade 1 tumour might avoid aggressive chemotherapy that would not significantly improve outcomes, while a person with a grade 3 NEC might need immediate systemic treatment.

Research and future directions

While grading provides essential prognostic information, researchers continue to refine the tools we use to assess tumour behaviour.

Emerging biomarkers

Molecular profiling is uncovering genetic and epigenetic changes linked to NET aggressiveness. Mutations in genes like DAXX, ATRX, TP53, and RB1 are being studied for their prognostic significance. Epigenetic markers and circulating tumour DNA (ctDNA) are also being explored as potential tools for real-time monitoring.

Improving grading accuracy

One challenge is tumour heterogeneity. Different parts of the same tumour, or different metastases, can show different Ki-67 values. Advances in digital pathology and artificial intelligence may help reduce variability by standardising how Ki-67 is measured and reported.

Towards personalised prognostics

The ultimate goal is to move beyond broad categories and develop personalised prognostic models that integrate grade, stage, biomarkers, imaging, and patient-specific factors. This would enable clinicians to provide more accurate predictions and more precisely tailored therapies.

The prognostic significance of tumour grade in neuroendocrine cancers cannot be overstated. Grade provides a crucial lens through which clinicians assess risk, select treatments, and plan long-term follow-up. For patients, understanding their tumour grade offers clarity in an often confusing journey, helping to frame expectations and guide informed choices.

As research progresses, grading systems will likely become more sophisticated, incorporating molecular insights alongside traditional pathology. This evolution holds promise for more accurate predictions, more personalised care, and ultimately, better outcomes for people living with NETs.

Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line.

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