Some neuroendocrine tumours (NETs) are considered less common cancers, but certain subtypes are even less common due to their unusual locations and variable symptoms. While the majority of NETs are found in the digestive system, pancreas, and lungs, some develop in sites such as the thymus, kidney, breast, and genitourinary system. These rare NETs present unique diagnostic challenges, often leading to delayed detection and misdiagnosis.
Unlike more common cancers, NETs can grow slowly and produce fluctuating hormone levels, making them difficult to identify using conventional diagnostic tools. In some cases, patients experience non-specific symptoms that mimic more common conditions, leading to long periods of uncertainty before a correct diagnosis is made. Additionally, healthcare providers may not be familiar with rare NET subtypes, further complicating early recognition.
This article explores the specific challenges in diagnosing rare NETs, the limitations of standard diagnostic methods, and emerging strategies aimed at improving detection and patient outcomes.
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 rare NETs
Neuroendocrine tumours arise from neuroendocrine cells, which are found throughout the body. While most NETs occur in the pancreas, lungs, and gastrointestinal tract, some develop in less typical locations, making them harder to detect. A NET is considered rare when it arises in an uncommon site or has distinct biological behaviour compared to more frequently diagnosed NETs.
Examples of uncommon NET sites
- Thymic NETs – Located in the thymus gland in the chest, these tumours are often aggressive but difficult to detect early.
- Renal (kidney) NETs – Extremely rare, often found incidentally on imaging scans.
- Breast NETs – Frequently mistaken for conventional breast cancer due to overlapping symptoms.
- Genitourinary NETs (bladder, prostate, kidney, testicular) – Present with urinary symptoms or hormone-related changes, often leading to delayed diagnosis.
Since NETs in these locations are rarely considered during initial medical evaluations, patients frequently undergo extensive testing for other conditions before the correct diagnosis is made.
Non-specific and overlapping symptoms
Rare NETs often produce vague symptoms that are mistaken for more common illnesses. Depending on the tumour location, symptoms may include:
- Chronic cough or chest pain (thymic NETs) misdiagnosed as asthma or lung infection.
- Flank pain and haematuria (renal NETs) mistaken for kidney stones.
- Pelvic pain and urinary urgency (bladder or prostate NETs) diagnosed as a urinary tract infection.
- Unexplained weight gain and facial swelling (hormone-secreting NETs) attributed to metabolic disorders.
Due to symptom overlap, many patients undergo treatment for unrelated conditions for months or even years before receiving an accurate NET diagnosis.
Impact of delayed symptom recognition
The longer a NET goes undiagnosed, the greater the chance of tumour progression and metastasis. Many NETs do not cause symptoms until they reach an advanced stage, further complicating early detection. Delayed symptom recognition can also lead to:
- Increased tumour burden, reducing treatment options.
- Longer diagnostic pathways, requiring multiple referrals and tests.
- Greater physical and emotional distress for patients.
Since rare NETs may not be considered in the initial differential diagnosis, primary care physicians and specialists must maintain a high index of suspicion when patients present with persistent, unexplained symptoms.
Limited awareness among healthcare providers
Most general practitioners and even some oncologists have limited exposure to rare NETs, given their low incidence rates. This contributes to:
- Underdiagnosis, where symptoms are dismissed as benign.
- Misdiagnosis, leading to inappropriate treatments for unrelated conditions.
- Missed opportunities for early intervention, particularly when symptoms are attributed to more common diseases.
Importance of specialist referral
Patients with suspected rare NETs should be referred to NET specialist centres, where multidisciplinary teams (MDTs) include:
- Oncologists with NET expertise.
- Endocrinologists for hormone-secreting tumours.
- Radiologists skilled in advanced NET imaging.
- Pathologists experienced in NET classification.
- Surgeons with experience in NET-related procedures.
- Gastroenterologists for gastrointestinal NETs.
- Respiratory physicians for lung and thoracic NETs.
Referral to a NET specialist team can significantly improve diagnostic accuracy and treatment planning.
Difficulties with imaging and detection
Many NETs are small and slow-growing, which makes them:
- Hard to visualise on standard imaging (e.g., CT and MRI scans).
- Easily mistaken for benign lesions.
- More challenging to diagnose before they spread.
Limitations of standard imaging for rare locations
Conventional CT and MRI may not detect small NETs, particularly in the thymus, kidney, or breast.
- Functional imaging, such as Gallium-68 DOTATATE PET/CT, is often required for accurate localisation.
- Endoscopic ultrasound (EUS) may be necessary for detecting small pancreatic or gastrointestinal NETs.
Imaging challenges can delay diagnosis, requiring patients to undergo multiple scans over time before a tumour is identified.
Challenges in biomarker identification
Unlike pancreatic and functioning NETs, which produce recognisable hormone syndromes, rare NETs may have:
- Variable hormone secretion, making biomarker detection unreliable.
- Fluctuating levels of Chromogranin A (CgA), a commonly used NET biomarker.
Limitations of traditional blood and urine tests
- 5-HIAA tests (used for serotonin-producing NETs) may be unhelpful for non-functional tumours.
- CgA can be falsely elevated due to proton pump inhibitor (PPI) use, leading to false positives.
Given these challenges, genetic and molecular profiling is increasingly used to identify NET-specific markers.
Complexities in tissue diagnosis
Some rare NETs are deeply located and difficult to biopsy without advanced techniques. Challenges include:
- Thymic NETs, which require surgical access due to their position in the mediastinum.
- Renal NETs, where biopsy poses a risk of bleeding or tumour seeding.
- Small, scattered tumours that may not be easily sampled.
Need for advanced pathological expertise
Since rare NETs share features with other cancers, expert pathological analysis is required to confirm:
- NET differentiation (well vs. poorly differentiated).
- Proliferation rates (Ki-67 index).
- Hormone expression patterns.
Without precise histological evaluation, NETs may be misclassified, leading to incorrect treatment decisions.
Impact of delayed or missed diagnosis
The biggest risk of diagnostic delay is disease progression, which can result in:
- Larger tumours requiring more aggressive treatments.
- Higher rates of metastasis to the liver, lungs, or bones.
- Reduced treatment success and poorer prognosis.
Effect on treatment options and prognosis
Late-stage NETs may no longer be eligible for surgery, requiring systemic treatments such as somatostatin analogues, PRRT, or chemotherapy.
Improving diagnosis of rare NETs
Diagnosis of rare NETS is improving all the time, and requires a collaborative diagnostic approach, involving:
- NET oncologists and endocrinologists.
- Radiologists using advanced functional imaging.
- Pathologists trained in neuroendocrine tumour classification.
Advances in imaging and diagnostic techniques
- Gallium-68 DOTATATE PET/CT has greatly improved NET detection.
- AI-based imaging techniques are enhancing tumour identification.
- Liquid biopsy and molecular testing offer new diagnostic possibilities.
Education and awareness for clinicians
Ongoing training and greater awareness among primary care doctors and oncologists can help reduce diagnostic delays, ensuring that rare NETs are detected earlier and treated more effectively.
Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line.
SOURCES
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