Anatomic Distribution of Neuroendocrine Tumours

Neuroendocrine tumours (NETs) are a diverse group of neoplasms originating from neuroendocrine cells, which possess characteristics of both nerve and endocrine cells.

These cells are distributed throughout the body, leading to NETs arising in various anatomical locations.

Understanding the distribution of NETs is crucial for accurate diagnosis and effective management.

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.

Overview of neuroendocrine tumour origins

Neuroendocrine cells are specialised cells that release hormones into the blood in response to signals from the nervous system.

They are found in numerous organs, including the gastrointestinal (GI) tract, pancreas, lungs, and other tissues.

Consequently, NETs can develop in multiple regions, with varying clinical presentations and behaviours.

Gastrointestinal (GI) tract NETs

The GI tract is the most common site for NETs, accounting for a significant proportion of cases. Within the GI tract, NETs frequently occur in the small intestine, rectum, and appendix.

Small intestine

NETs of the small intestine, particularly the ileum, are among the most prevalent. These tumours often present late due to nonspecific symptoms such as abdominal discomfort, leading to delayed diagnosis. They have a higher propensity for metastasis compared to NETs in other GI locations.

Rectum

Rectal NETs are commonly detected during routine screenings, such as colonoscopies. They tend to be smaller and less aggressive, often identified incidentally. Early detection generally leads to a favourable prognosis.

Appendix

Appendiceal NETs are frequently discovered incidentally during appendectomies performed for acute appendicitis. These tumours are typically small and have a low risk of metastasis, contributing to an excellent prognosis.

Pancreatic neuroendocrine tumours (pNETs)

Pancreatic NETs originate from the hormone-producing cells of the pancreas and are classified based on their functional status.

Functional pNETs

Functional pNETs secrete hormones leading to distinct clinical syndromes. Examples include insulinomas (insulin-producing), gastrinomas (gastrin-producing), and glucagonomas (glucagon-producing). These tumours often present with symptoms related to hormone hypersecretion, facilitating earlier diagnosis.

Nonfunctional pNETs

Nonfunctional pNETs do not produce excessive hormones, making them more challenging to detect. They often grow larger before causing symptoms due to mass effect, leading to later-stage diagnosis. Despite this, they can be less aggressive than their functional counterparts.

Lung and bronchial NETs

The lungs are the second most common location for NETs, with pulmonary carcinoid tumours representing a notable subset. These tumours are divided into typical and atypical carcinoids based on their histological characteristics.

Typical carcinoids

Typical carcinoids are well-differentiated, slow-growing tumours that rarely metastasise. They account for the majority of pulmonary carcinoids and are often located centrally in the bronchial airways. Surgical resection is commonly curative, and the prognosis is generally favourable.

Atypical carcinoids

Atypical carcinoids are less common and exhibit a higher mitotic rate, making them more aggressive with a greater likelihood of metastasis. They may present with symptoms such as cough, wheezing, or haemoptysis. Early detection and treatment are crucial for improving outcomes.

Other sites of NETs

While the GI tract, pancreas, and lungs are the predominant sites for NETs, these tumours can also arise in other organs, including the thymus, thyroid, adrenal glands, and genitourinary system. The clinical behaviour and prognosis of NETs in these locations vary, necessitating individualised approaches to management.

Understanding the anatomic distribution of NETs is essential for clinicians to facilitate prompt diagnosis, tailor treatment strategies, and optimise patient outcomes.

Thymus and mediastinum NETs

Neuroendocrine tumours arising in the thymus and mediastinum are rare but clinically significant due to their potential aggressiveness.

The thymus is a small organ located in the anterior mediastinum, playing a role in immune function during early life. Although uncommon, thymic NETs (also known as thymic carcinoids) can behave aggressively and often present at an advanced stage.

These tumours are more frequently diagnosed in men and are sometimes associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1). Symptoms can include chest pain, persistent cough, or breathing difficulties, although many cases are asymptomatic and detected incidentally through imaging for unrelated conditions.

Thymic NETs have a higher propensity to metastasise compared to other NET types, and treatment typically involves surgical resection. In some cases, adjuvant radiotherapy or chemotherapy may be required. Because of their rarity, treatment should be managed by a multidisciplinary team familiar with neuroendocrine malignancies.

Genitourinary and reproductive system NETs

NETs of the genitourinary and reproductive systems are rare and can occur in organs such as the bladder, prostate, cervix, uterus, and ovaries. These tumours often mimic more common cancers in these locations, making accurate diagnosis a challenge.

Bladder NETs are typically aggressive and may present with haematuria (blood in the urine) or urinary frequency. Prostatic NETs, though rare, tend to be poorly differentiated and can occur alongside conventional adenocarcinomas of the prostate. Symptoms may include pelvic discomfort, difficulty urinating, or changes in urinary habits.

In females, NETs may develop in the cervix or ovaries. Cervical NETs are usually high-grade and aggressive, often requiring a combination of surgery, chemotherapy, and radiotherapy. Ovarian carcinoid tumours are uncommon and may be associated with hormonal syndromes such as carcinoid syndrome if bioactive substances are secreted.

Due to the diversity of locations and behaviours, treatment for genitourinary and reproductive NETs is highly individualised. Histopathological evaluation and accurate classification are essential to guide appropriate therapy.

Hepatic (liver) involvement in NETs

The liver is one of the most common sites for neuroendocrine tumour metastases, especially from gastrointestinal or pancreatic primary NETs. While primary hepatic NETs do exist, they are exceedingly rare. Most liver involvement occurs when tumours spread from other parts of the body, particularly from the small intestine, pancreas, or colon.

Liver metastases may present with nonspecific symptoms such as abdominal discomfort, fatigue, or hepatomegaly (enlarged liver). In some cases, patients develop carcinoid syndrome, characterised by flushing, diarrhoea, and wheezing when liver metastases release serotonin or other vasoactive substances directly into the bloodstream.

Diagnosis often involves imaging studies such as MRI or Ga-68 DOTATATE PET/CT scans, alongside biomarker testing for chromogranin A and serotonin levels. Treatment options include surgical resection of metastases where possible, hepatic artery embolisation, systemic therapies such as somatostatin analogues, and peptide receptor radionuclide therapy (PRRT).

Managing liver metastases is central to improving quality of life and prolonging survival in many NET patients, highlighting the importance of early detection and specialised care.

Cutaneous and unknown primary NETs

While rare, some NETs originate in the skin. The most well-known example is Merkel cell carcinoma (MCC), a highly aggressive cutaneous neuroendocrine carcinoma. MCC typically presents as a rapidly growing, painless skin nodule, often on sun-exposed areas such as the head, neck, or arms. It is more common in older adults and those with weakened immune systems.

MCC is associated with Merkel cell polyomavirus in many cases and is characterised by its aggressive nature and high recurrence rate. Treatment usually involves wide local excision, lymph node assessment, radiotherapy, and in some cases, immune checkpoint inhibitors.

Another diagnostic challenge is NETs with unknown primary origins. These are metastatic neuroendocrine tumours where no primary tumour can be identified despite comprehensive imaging and diagnostic work-up. The liver, lymph nodes, or bones may be the first detected sites, but the original tumour location remains elusive.

In such cases, Ga-68 DOTATATE PET/CT and endoscopic investigations may help identify the primary. However, even if the origin remains unknown, treatment can still be guided by the tumour’s grade, histology, and biomarker profile. Management often mirrors that of NETs from more common sites, with a focus on symptom control and disease progression.

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