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Factors Influencing Prognosis in Neuroendocrine Tumours

When someone is diagnosed with neuroendocrine cancer (NETs), one of the first questions often asked is: What does this mean for my future? While no two NETs behave exactly the same, there are several well-established factors that help clinicians estimate how a tumour might behave and how a person might respond to treatment. 

Understanding these factors can help people living with NETs make informed decisions, seek timely care, and advocate for their best possible outcomes.

Let’s explore the major factors that influence prognosis in people with neuroendocrine cancer, including tumour location, stage, grade, hormone activity, and treatment response, as well as the evolving role of research in shaping outcomes.

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.

Tumour location and type

Neuroendocrine tumours can arise almost anywhere in the body, but they’re most commonly found in the gastrointestinal (GI) tract, pancreas, or lungs. These sites each come with their own challenges, risks, and treatment options.

For example:

  • Small Bowel NETs (SB-NETs) are often slow-growing but may be diagnosed late due to vague symptoms like diarrhoea, bloating or intermittent pain. 
  • Pancreatic NETs (PNETs) are more likely to be detected earlier due to hormone-related symptoms, but they can vary greatly in how quickly they grow and spread.
  • Pulmonary NETs, arising in the lungs, include typical and atypical carcinoids and may be confused with asthma or chronic obstructive pulmonary disease (COPD) before diagnosis.

Some NETs arise in rare locations such as the rectum, appendix, thymus, or ovaries. These may behave differently again and might not be recognised immediately by clinicians unfamiliar with the disease.

Why location matters:

  • It influences the type of surgery available and whether complete resection is possible.
  • It affects the likelihood of early vs late detection.
  • It shapes the expected biological behaviour of the tumour.

Stage at diagnosis

One of the most important prognostic indicators is whether the tumour is localised (confined to its site of origin), regionally advanced (spread to nearby lymph nodes), or metastatic (spread to distant organs such as the liver, bones, or lungs).

Unfortunately, many NETs are diagnosed after they’ve already spread. According to the SEER database, over 50% of patients with GI or pancreatic NETs are diagnosed with metastatic disease. However, compared to many other cancers, even metastatic NETs can sometimes be managed over long periods, depending on tumour grade and access to appropriate care.

Survival and staging:

  • People with localised NETs typically have much better survival rates.
  • Early-stage NETs may be cured through surgery alone.
  • Metastatic NETs may still have a favourable prognosis, especially if slow-growing and well-differentiated.

This highlights the importance of early detection and raising awareness among both the public and general practitioners, who are often the first point of contact.

Tumour grade and Ki-67 index

Grading refers to how aggressive a tumour looks under the microscope. In NETs, this is most commonly measured using the Ki-67 proliferation index, which estimates how quickly tumour cells are dividing. The higher the Ki-67, the more rapidly the tumour is growing.

  • Grade 1 NETs: Ki-67 ≤2% – slow-growing, often slow to develop.
  • Grade 2 NETs: Ki-67 between 3–20% – intermediate growth rate.
  • Grade 3 NETs: Ki-67 >20% – fast-growing, potentially more aggressive.

Importantly, grade 3 tumours are further split into two types: well-differentiated NETs (which look more like normal cells) and poorly differentiated neuroendocrine carcinomas (NECs), which tend to behave more like traditional aggressive cancers.

Prognostic implications:

  • Low-grade NETs may remain stable for many years.
  • High-grade NETs and NECs often require intensive treatment and have a poorer prognosis.
  • Accurate Ki-67 scoring is essential to guide therapy and expectations.

Hormonal activity of the tumour

NETs are often classified as either functioning or non-functioning, depending on whether they produce hormones that cause noticeable symptoms. 

Hormone secretion can lead to symptoms that prompt earlier diagnosis in some cases. For example, an insulinoma may be detected due to episodes of low blood sugar. However, hormone-related symptoms can also significantly affect quality of life and increase the risk of complications like carcinoid heart disease or diarrhoea-related malnutrition.

Clinical impact:

  • Hormone-producing tumours may trigger earlier diagnosis and intervention.
  • Chronic symptoms may impact nutritional status, mental health, and cardiac function.
  • Biochemical markers (e.g. chromogranin A, 5-HIAA) can be useful in tracking disease activity but may not always correlate with tumour burden.

Treatment response and access to therapies

A person’s outlook can also depend on how well their disease responds to available treatments. Surgery remains the mainstay for localised NETs and may be used for symptom control in some metastatic cases.

Other therapies that influence survival include:

  • Somatostatin analogues (SSAs) such as octreotide and lanreotide
  • Peptide receptor radionuclide therapy (PRRT) for somatostatin receptor–positive tumours
  • Targeted therapies like everolimus and sunitinib (especially in pancreatic NETs)
  • Chemotherapy, typically used for more higher grade or poorly differentiated tumours
  • Ablation, embolisation, or liver-directed therapies in cases of liver-dominant disease

Multidisciplinary care, including input from oncologists, endocrinologists, surgeons, nuclear medicine specialists, and specialist nurses, can dramatically improve outcomes.

Key takeaway:

  • The more tailored and timely the treatment plan, the better the potential outcome.
  • Some patients may not be able to access therapies like PRRT due to locations and accessibility which can influence prognosis.
  • Some patients may not be able to access therapies like PRRT or targeted drugs due to their tumours lacking the receptors needed for these treatments to be effective.
  • Centres of excellence and NET-specialist teams can significantly enhance patient care.

Patient factors

It’s not just the tumour that determines prognosis: patient-specific factors also play an important role and can influence treatment decisions and ultimately prognosis. These include:

  • Age: Older adults may have less physiological reserve 
  • General health: Co-morbidities 
  • Co-existing conditions: Heart disease, diabetes, or immunosuppression can influence treatment choices and recovery.

Patients with strong support networks, early palliative involvement, and access to comprehensive care may be better equipped to manage the emotional and physical demands of living with NETs.

Ongoing research and future directions

The future of neuroendocrine cancer care is increasingly personalised. As researchers uncover more about tumour biology, molecular profiling, and immune signatures, there is growing hope that targeted treatments will become more widely available.

Emerging areas of research include:

  • New biomarkers to better predict prognosis and treatment response
  • Liquid biopsies for real-time tumour monitoring
  • Next-generation PRRT using alpha-emitters
  • Immunotherapies, particularly in combination with other treatments
  • Artificial intelligence and digital pathology to support more accurate grading and diagnosis

Clinical trials are essential to advancing the field. They not only provide access to promising treatments but also help shape the future standard of care for NET patients around the world.

While no two NETs are alike, understanding the key prognostic factors can empower people with NETs to ask informed questions and seek expert care. Tumour location, stage, grade, hormone activity, treatment options, and personal health all interact to shape the likely path ahead.

Importantly, prognosis is not fixed. It can evolve over time, especially as new therapies emerge and more tailored approaches become available. With ongoing research, a growing network of specialist centres, and a better-informed public, the outlook for people living with neuroendocrine tumours continues to improve.

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

SOURCES

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The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis.
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Ki‑67 index variability in neuroendocrine tumors.
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