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Home » Differential Diagnosis of NETs

Differential Diagnosis of NETs

Neuroendocrine tumours (NETs) remain a complex and often misunderstood group of cancers. While they are increasingly recognised in Australia, diagnosis remains challenging, largely because NET symptoms frequently mimic more common conditions.

Understanding the importance of differential diagnosis is critical to achieving timely detection, correct treatment pathways, and better patient outcomes. 

This article explores how NETs are differentiated from other diseases, the tools used to achieve accurate diagnosis, and the clinical implications of getting it right.

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.

Understanding the need for differential diagnosis

NETs can arise almost anywhere in the body where neuroendocrine cells are present. Because these tumours often produce hormones or peptides, they may trigger a range of non-specific symptoms: diarrhoea, cramping, flushing, fatigue, or palpitations. Many of these overlap with far more common benign conditions, leading to diagnostic delays. In some cases, patients may see multiple specialists over several years before a NET diagnosis is finally made.

This overlap means that clinicians must always consider a broad differential diagnosis when patients present with unexplained, persistent, or fluctuating symptoms. Missing the NET diagnosis risks delaying potentially life-saving treatment.

NETs misdiagnosed as common conditions

There is a range of highly common conditions that are misdiagnosed as NETs, and vice versa.

Irritable Bowel Syndrome (IBS)

IBS is one of the most frequent misdiagnoses for patients who later turn out to have gastrointestinal NETs. Symptoms such as chronic diarrhoea, abdominal cramping, bloating, and alternating bowel habits are hallmarks of both conditions. 

Because IBS is so common and typically benign, it is often diagnosed first, particularly in younger patients. However, when symptoms persist or worsen despite typical IBS management, further investigation for NETs may be warranted.

Anxiety disorders

NETs that secrete serotonin, catecholamines, or other hormones may produce episodes of flushing, palpitations, sweating, and anxiety-like symptoms. These can easily be misattributed to panic attacks or generalised anxiety disorder. 

In fact, many patients with functional NETs describe being treated for anxiety for months or years before further investigations reveal a hormonal cause.

Menopause

For women, particularly those in midlife, NET symptoms can closely resemble menopausal changes. Hot flushes, mood fluctuations, and fatigue are often dismissed as part of the natural ageing process. 

However, understanding the characteristics of flushing can help differentiate between the two. Menopausal flushing is typically associated with sweating (“wet flushing”), while NET-related flushing is usually “dry,” occurring without perspiration and often affecting the face and upper chest. 

This distinction, along with other symptoms, can support more accurate diagnosis.

Inflammatory Bowel Disease (IBD)

Conditions such as Crohn’s disease or ulcerative colitis share many symptoms with gastrointestinal NETs: abdominal pain, diarrhoea, weight loss, and nutritional deficiencies. In some cases, mild NETs may coexist with IBD, further complicating diagnosis. Imaging and biopsy are usually required to definitively rule out or confirm NETs in these scenarios.

Thyroid disorders

Thyroid conditions, both hyperthyroidism and hypothyroidism, can produce fatigue, weight changes, heat intolerance, or palpitations, much like functional NETs. A detailed hormonal work-up, combined with imaging and NET-specific markers, often helps differentiate between thyroid dysfunction and NET-related hormone secretion.

Diagnostic tools to distinguish NETs

Because NETs mimic so many conditions, accurate diagnosis often relies on combining clinical evaluation with specialised tests.

Biochemical markers

Biochemical testing is one of the key pillars in differentiating NETs from other disorders. Two of the most widely used markers are:

  • Chromogranin A (CgA): This general marker of neuroendocrine activity can be elevated in many NETs but must be interpreted carefully, as levels may also rise due to other factors (e.g. proton pump inhibitor use or renal insufficiency).
  • 5-Hydroxyindoleacetic acid (5-HIAA): Measured in a 24-hour urine collection or blood test, this serotonin metabolite is particularly useful for detecting carcinoid syndrome associated with serotonin-secreting NETs.

Other hormone markers may be assessed depending on the suspected NET type, including gastrin, insulin, glucagon, vasoactive intestinal peptide (VIP), and pancreatic polypeptide.

Imaging techniques

Functional imaging plays a critical role in NET diagnosis. While conventional CT or MRI may identify masses or metastases, they may miss smaller or early-stage tumours.

  • Ga-68 DOTATATE PET/CT has emerged as the gold standard for many NETs. This scan targets somatostatin receptors on tumour cells, offering exceptional sensitivity and specificity compared to older techniques.
  • Octreoscan (SRS), though still used in some centres, has largely been surpassed by Ga-68 PET for diagnostic purposes.
  • FDG PET/CT may be used in higher-grade, more aggressive NETs where glucose uptake is increased.

These imaging tools not only aid diagnosis but are also valuable in staging and guiding treatment.

Endoscopy and histopathology

For gastrointestinal NETs, endoscopic procedures (gastroscopy, colonoscopy, endoscopic ultrasound) enable direct tumour visualisation and biopsy. Obtaining tissue allows for definitive histological confirmation, assessment of tumour grade, and evaluation of Ki-67 proliferation index, which informs prognosis and treatment planning.

Histopathology remains the gold standard in confirming a NET diagnosis, distinguishing it from other tumour types, and accurately subtyping it according to WHO classification.

Importance of a multidisciplinary approach

Given the complexity of NETs, accurate diagnosis usually involves multiple specialists:

  • General practitioners
  • Gastroenterologist
  • Endocrinologists
  • Oncologists
  • Radiologists
  • Nuclear medicine physicians
  • Pathologists
  • NET specialist nurses

A coordinated, multidisciplinary approach ensures that all available clinical, biochemical, imaging, and histological data are reviewed in tandem, significantly improving diagnostic accuracy and reducing misdiagnosis rates.

Challenges and considerations

Tumour heterogeneity

NETs are highly variable depending on location, grade, hormonal activity, and metastatic spread. This diversity often complicates diagnosis, as two patients with NETs may present entirely differently. Functional NETs produce hormones causing systemic symptoms, while non-functional NETs may remain silent until large or metastatic.

Rare NET presentations

Some NETs arise in unusual locations such as the thymus, genitourinary tract, breast, or skin (Merkel cell carcinoma). In these rare cases, clinicians may not initially consider a neuroendocrine origin, increasing the risk of diagnostic delay or misclassification.

Evolving diagnostic guidelines

As NET research advances, new biomarkers, imaging protocols, and molecular techniques continue to emerge. Guidelines are regularly updated by global bodies, such as the European Neuroendocrine Tumour Society (ENETS) and the National Comprehensive Cancer Network (NCCN) in the US, to reflect best practices in diagnostic work-up.

Clinical implications of accurate diagnosis

Avoiding delayed treatment

A delayed NET diagnosis may allow the tumour to progress, metastasise, or cause debilitating hormonal syndromes. Early identification allows for:

  • Potential curative surgery
  • Timely access to PRRT, SSAs, or targeted therapies
  • Better control of hormone-related symptoms

Ensuring appropriate therapy selection

Treatment for NETs differs markedly from other cancers and non-cancer conditions. Accurate diagnosis ensures that patients receive tailored therapies based on:

  • Tumour site and type
  • Functionality (hormone secretion)
  • Stage of disease
  • Tumour grade and Ki-67 index

For example, low-grade localised NETs may be managed surgically, while high-grade NETs require aggressive systemic treatment.

Improving awareness and education

Public and clinician awareness remains one of the biggest opportunities for improving NET outcomes. With better understanding of NET symptom overlap, more Australians experiencing unexplained or chronic symptoms may undergo appropriate testing sooner.

Organisations like NeuroEndocrine Cancer Australia continue to play a vital role in promoting education, supporting patients, and advocating for improved diagnostic access.

Differential diagnosis remains one of the most critical and challenging aspects of neuroendocrine cancer care. With symptoms that often mimic far more common conditions, NETs require careful evaluation using a combination of clinical judgment, biochemical markers, imaging, histopathology, and multidisciplinary collaboration. 

Early and accurate diagnosis offers the best chance at effective treatment and long-term management, ultimately improving outcomes for Australians living with this complex disease.

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

Sources

Modlin IM, et al.
“Neuroendocrine tumors of the small intestine and appendix: an epidemiological report based on the SEER database.”
World Journal of Gastroenterology, 2013.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696056/

Pavel M, et al.
“ENETS Consensus Guidelines for Standard of Care in Neuroendocrine Neoplasms: 2020 update.”
Neuroendocrinology, 2020.
https://www.karger.com/Article/FullText/506347

Lawrence B, et al.
“The epidemiology of neuroendocrine tumors.”
Endocrinol Metab Clin North Am, 2011.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037028/

Warner RR.
“Clinical approach to functional neuroendocrine tumors.”
Cleveland Clinic Journal of Medicine, 2017.
https://www.ccjm.org/content/84/9_suppl_3/12S

Basuroy R, et al.
“The clinical course of neuroendocrine tumors of the gastrointestinal tract.”
Endocrine-Related Cancer, 2014.
https://erc.bioscientifica.com/view/journals/erc/21/3/21-3-R105.xml

Yao JC, et al.
“The role of imaging in the management of neuroendocrine tumors.”
The Lancet Oncology, 2008.
https://www.sciencedirect.com/science/article/abs/pii/S1470204508701930

Vinik AI, et al.
“Biochemical testing for neuroendocrine tumors.”
Pancreas Journal, 2010.
https://journals.lww.com/pancreasjournal/Abstract/2010/04000/Biochemical_Markers_in_the_Diagnosis_of.10.aspx

“The role of Ga-68 DOTATATE PET in diagnosis and management of NETs.”
Theranostics, 2017.
https://www.thno.org/v07p4081.htm 

“Consensus Guidelines for the Diagnosis and Management of Neuroendocrine Tumors: Multidisciplinary perspective.”
The Oncologist, 2018.
https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.2018-0252

NeuroEndocrine Cancer Australia.
“Diagnosis and management of neuroendocrine tumors in Australia.”
https://neuroendocrine.org.au/diagnosis/ 

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