Neuroendocrine Cancer Diagnosis

Neuroendocrine Cancer, though less common, holds significance in the realm of oncology due to its complex nature and diverse manifestations.

Neuroendocrine cancer can present with a myriad of symptoms, often varying depending on the location of the tumour within the body. Understanding the symptoms, diagnostic process, and collaborative efforts involved in confirming a diagnosis is crucial for individuals navigating this journey.

Recognising these symptoms early is key to initiating timely evaluation and intervention. From vague abdominal discomfort to more pronounced hormonal imbalances, any suspicious symptoms warrant prompt medical attention. Early detection not only facilitates timely treatment but also offers hope for a better prognosis and enhanced quality of life.

In this article, we’ll take a look at all the diagnostic factors that affect the lifetime of a neuroendocrine cancer diagnosis. For specific information related to your situation, get in touch with Neuroendocrine Cancer Australia’s NET nurse.

1. Symptoms and clinical presentation

The symptoms associated with neuroendocrine cancer can be diverse and nonspecific, making diagnosis challenging. Common manifestations may include abdominal pain, flushing, diarrhoea, and changes in bowel habits. 

However, the presentation can vary widely based on the site of the tumour. For example:

• Carcinoid tumours in the gastrointestinal tract may present with flushing and diarrhoea
• Pancreatic neuroendocrine tumours can cause abdominal pain and jaundice
• Symptoms of lung neuroendocrine cancers may manifest as coughing, chest pain, shortness of breath, wheezing, or recurrent respiratory infections

It’s crucial for individuals experiencing any concerning symptoms to seek medical evaluation without delay.

2. Initial evaluation and medical history

A comprehensive medical history serves as the starting point of the diagnostic process for neuroendocrine cancer. Healthcare providers meticulously gather information about symptoms, past medical conditions, family history, and potential risk factors. Understanding the patient’s medical background helps guide further evaluation and diagnostic testing, facilitating a more accurate diagnosis.

During the initial evaluation, healthcare providers inquire about symptoms such as abdominal pain, flushing, diarrhoea, and changes in weight or appetite. They also explore 

• The duration and progression of symptoms
• Any alleviating or exacerbating factors
• Associated signs such as jaundice or palpable masses

Additionally, past medical history, including any prior cancer diagnoses or relevant surgeries, will be thoroughly reviewed. Family history is also assessed to identify potential genetic predispositions to cancer, which may influence diagnostic and treatment decisions.

3. Physical examination and laboratory tests

Physical examination plays a vital role in identifying potential signs of neuroendocrine cancer. Healthcare providers may palpate the abdomen for masses or assess for signs of hormonal imbalances such as skin flushing or changes in blood pressure. 

Additionally, examination of the skin and mucous membranes may reveal characteristic findings associated with certain types of neuroendocrine cancer, such as carcinoid syndrome.

Laboratory tests, including blood and urine analyses, can provide valuable insights into hormone levels and biochemical markers indicative of Neuroendocrine Cancer. 

Blood tests may assess levels of hormones such as serotonin, chromogranin A, insulin, glucagon, and gastrin, which may be elevated in certain types of neuroendocrine cancer. 

Urine tests, such as 5-hydroxyindoleacetic acid (5-HIAA) measurement, can help detect metabolites of serotonin and other hormones excreted in the urine, aiding in the diagnosis and monitoring of carcinoid tumours.

You can learn more about the tests involved with neuroendocrine cancer by visiting our Optimal Care Pathway for people with NETs information.

4. Imaging studies

Imaging techniques such as CT scans, MRI scans, Octreotide scans, Ga68 Dotatate PET scans, and FDG PET scans are instrumental in diagnosing neuroendocrine cancer. These imaging modalities allow healthcare providers to visualise the:

• Location of the tumour
• Size of the tumour
• Grade and stage of the tumour

This visualisation aids in treatment planning and staging. It’s essential to select the most appropriate imaging modality based on the individual’s clinical presentation and suspected tumour location.

CT scans utilise X-rays to create detailed cross-sectional images of the body, providing information about the size and location of tumours as well as potential metastases to nearby organs or lymph nodes.

MRI scans use magnetic fields and radio waves to generate high-resolution images of soft tissues, offering superior contrast and detail compared to CT scans. 

Octreotide scans and Ga68 Dotatate PET scans involve the administration of radioactive tracers that bind to somatostatin receptors on neuroendocrine cancer cells, allowing for precise localisation and characterisation of tumours. These scans will be ordered by Specialists.

FDG PET scans utilise a radioactive tracer called fluorodeoxyglucose (FDG) to detect areas of increased glucose metabolism, which may indicate the presence of Neuroendocrine Cancer or metastatic lesions.These scans will be ordered by Specialists.

5. Biopsy and tissue sampling

Obtaining tissue samples through biopsy is crucial for confirming a diagnosis of neuroendocrine cancer. Endoscopic or surgical biopsies collect tissue samples for histological analysis. Pathology examination plays a pivotal role in confirming the presence of neuroendocrine tumour cells and determining tumour grade, which can influence treatment decisions.

During a biopsy procedure, a small sample of tissue is removed from the tumour or suspected lesion for examination under a microscope. The type of biopsy performed depends on the location and accessibility of the tumour as well as the preferences of the healthcare provider. 

Endoscopic biopsies, such as endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or endoscopic mucosal resection (EMR), may be used to sample tumours in the gastrointestinal tract or respiratory system. 

Surgical biopsies, such as core needle biopsy or excisional biopsy, may be performed to obtain larger tissue samples from deeper or inaccessible tumours.

Histological analysis of biopsy specimens involves staining the tissue with various dyes and examining it under a microscope to assess cellular characteristics and patterns of growth. Neuroendocrine Cancer cells typically exhibit features such as uniform round or oval shape, finely granular chromatin, and abundant cytoplasm with eosinophilic or amphophilic staining.

Immunohistochemical staining may be used to detect specific markers expressed by neuroendocrine cancer cells, such as chromogranin A, synaptophysin, and neuron-specific enolase (NSE). The results of histological analysis help confirm the diagnosis of neuroendocrine cancer and provide important prognostic information, including tumour grade and differentiation status.

6. Molecular and genetic testing

Molecular and genetic testing may provide further insights into the specific subtype of neuroendocrine cancer. Better yet, it may guide personalised treatment approaches for all types of neuroendocrine tumours. Understanding the genetic makeup of the tumour can inform targeted therapies and clinical trial eligibility.

Molecular testing of neuroendocrine cancer tumours may involve analysis of genetic mutations, chromosomal aberrations, and alterations in gene expression profiles. 

Next-generation sequencing (NGS) technologies enable comprehensive profiling of tumour genomes, identifying actionable mutations and potential therapeutic targets. 

Targeted therapies directed against specific molecular targets, such as somatostatin receptors, tyrosine kinase receptors, or mammalian target of rapamycin (mTOR) pathways, have shown promise in the treatment of Neuroendocrine Cancer subtypes with specific molecular alterations. 

Clinical trials investigating novel targeted therapies and immunotherapies are ongoing, offering opportunities for patients to access innovative treatment options and contribute to the advancement of knowledge in the field.

Genetic testing may also be performed to assess the presence of hereditary cancer syndromes associated with an increased risk of developing neuroendocrine cancer. Germline mutations in genes such as MEN1, RET, VHL, NF1, and SDHx have been found in familial forms of neuroendocrine Cancer, such as:

• Multiple endocrine neoplasia type 1 (MEN1), 
• Hereditary paraganglioma-pheochromocytoma syndrome, 
• von Hippel-Lindau (VHL) disease, 
• Neurofibromatosis type 1 (NF1)
• Hereditary pheochromocytoma-paraganglioma syndrome. 

Genetic counselling and testing can help identify individuals at risk of hereditary cancer syndromes and inform screening and surveillance strategies for early detection and prevention.

7. Staging and grading

Staging and grading are essential components of the diagnostic process for Neuroendocrine Cancer. Staging and grading help determine the aggressiveness of the tumour based on histological characteristics, influencing treatment decisions and follow-up care.

The TNM staging system classifies tumours based on the size and extent of the primary tumour (T), involvement of nearby lymph nodes (N), and presence of distant metastases (M). 

• T-stage: Tumour size, depth of invasion, and spread to adjacent organs or tissues are evaluated. 
• N stage: Lymph node involvement is assessed based on the presence of tumour cells in regional lymph nodes. 
• M-stage: Distant metastases to organs such as the liver, lungs, bones, or brain are indicative of advanced disease.

TNM staging is not frequently utilised in NETs. NETs are commonly classified as stages:

• Stage 1 – the cancer has not spread.
• Stage 2 – the cancer has grown into nearby organs but not into the lymph nodes.
• Stage 3 – the cancer has spread to the lymph nodes but not to distant parts of the body
• Stage 4 – cancer may or may not have spread to lymph nodes. it has spread to distant parts of the body.

Grading of Neuroendocrine Cancer tumours is based on histological features such as cellular differentiation and proliferation rate. Well-differentiated neuroendocrine tumours (NETs) are classified as grade 1 or grade 2 based on the Ki-67 proliferation index and mitotic count. 

• Grade 1 NETs have a low proliferative rate (<3% Ki-67 index) and are associated with indolent behaviour and favourable prognosis
• Grade 2 NETs have a higher proliferative rate (3-20% Ki-67 index) and may exhibit more aggressive clinical behaviour. 
• Grade 3 NETs are poorly differentiated and classified as with a high proliferative rate (>20% Ki-67 index).
• Grade 3 NECs (neuroendocrine carcinoma) are poorly differentiated and classified as with a high proliferative rate (>20% Ki-67 index).

Treatment options vary depending on the stage and grade of the tumour, with early-stage, well-differentiated NETs often managed with surgical resection and localised therapies. Advanced-stage or poorly differentiated NECs may require systemic therapies such as chemotherapy, targeted therapy, or peptide receptor radionuclide therapy (PRRT).

8. Differential diagnosis

Given the diverse clinical presentation of neuroendocrine cancer, it’s essential to consider other conditions that may mimic its symptoms. A multidisciplinary approach involving specialists from various disciplines ensures comprehensive evaluation and accurate diagnosis.

Dozens of conditions may mirror the symptoms of neuroendocrine cancer in the bowel, all of which may present with abdominal pain, diarrhoea, and other gastrointestinal symptoms similar to those seen with NETs. Here are some of them:

• Irritable bowel syndrome,
• Gastritis
• Inflammatory bowel disease
• Peptic ulcer disease
• Infectious gastroenteritis
• Other gastrointestinal malignancies

Differential diagnosis of Neuroendocrine Cancer involves ruling out other possible causes of symptoms based on clinical presentation, imaging findings, laboratory tests, and histological analysis. In the end, everything must be done to reveal the specific biochemical abnormalities associated with certain conditions.

9. Confirming the diagnosis

Confirming a diagnosis of neuroendocrine cancer involves a collaborative effort among healthcare professionals, including oncologists, pathologists, radiologists, and surgeons. A definitive diagnosis paves the way for tailored treatment strategies and ongoing management.

The process of confirming a diagnosis of neuroendocrine cancer begins with the following:

1. The recognition of symptoms based on physical examination findings and laboratory tests
2. Imaging studies such as CT scans, MRI scans, and nuclear medicine scans to reveal the presence of tumours and provide information about their size, location, and extent of spread
3. Biopsy and tissue sampling for histological confirmation of neuroendocrine cancer and determination of tumour grade and differentiation status.

The results of diagnostic tests and histological analysis are reviewed by a multidisciplinary team of healthcare professionals, including oncologists, pathologists, radiologists, and surgeons, to confirm the diagnosis of neuroendocrine cancer and develop a personalised treatment plan. 

10. Finding support

Navigating the path to understanding neuroendocrine cancer diagnosis requires patience, diligence, and unwavering support between patients, their families, and their care team. 

Following a neuroendocrine cancer diagnosis, seeking support is paramount for navigating the challenges ahead. 

Healthcare providers are a valuable resource, offering guidance on treatment options and connecting patients with support groups, counselling services, and educational materials. 

Support groups, whether in-person or online, provide a platform for individuals to connect with others in similar situations, share experiences, and offer mutual encouragement.

In essence, finding support after diagnosis involves reaching out to others, both within and outside the medical community, and actively seeking resources and activities that promote physical, emotional, and psychological well-being

By prioritising early detection, comprehensive evaluation, and multidisciplinary collaboration, individuals affected by neuroendocrine cancer can embark on a journey towards effective treatment and improved quality of life. 

Neuroendocrine Cancer Australia is proud to advocate and support all people dealing with neuroendocrine cancer. Together, we stand committed to providing compassionate care and empowering individuals on their journey to healing.