Neuroendocrine cancer of the ovary and endometrium

Neuroendocrine cancer of the ovary and uterus refers to rare and often aggressive cancers that develop from specialised neuroendocrine cells within the female reproductive tract. These cancers account for less than 2 per cent of all gynaecological cancers.

Because neuroendocrine cells are found throughout many organs of the body, one of the first and most important questions in managing these cancers is whether a pelvic neuroendocrine tumour is a primary cancer (one that has started in the ovary or uterus) or a secondary (metastatic) cancer that has spread from another site such as the gastrointestinal tract or lungs. This distinction significantly affects treatment planning and outcomes.

Gynaecological neuroendocrine cancers are often found at a later stage because their symptoms can resemble more common gynaecological conditions and are frequently attributed to other causes. Some people also develop symptoms related to hormone overproduction, including carcinoid syndrome and, in advanced cases, carcinoid heart disease.

At NeuroEndocrine Cancer Australia (NECA), we support people diagnosed with gynaecological neuroendocrine cancer and their families through education, resources, advocacy, and access to the NET Nurse, counsellor and dietitian services.

Understanding neuroendocrine cancer of the ovary and uterus

Neuroendocrine cells are found throughout the body, including within the female reproductive tract. These specialised cells combine characteristics of nerve cells and hormone-producing cells, and can release hormones and other biologically active substances into the bloodstream.

When neuroendocrine cells in the ovary or uterus grow abnormally and form tumours, they are classified as gynaecological neuroendocrine neoplasms, or neuroendocrine cancers. These include both neuroendocrine tumours (NETs) and the more aggressive neuroendocrine carcinomas (NECs). These cancers can vary enormously in how quickly they grow, whether they produce hormones, and how likely they are to spread.

Because these cancers are so rare, there are limited condition-specific clinical guidelines. Treatment decisions are often guided by principles drawn from neuroendocrine cancers at other sites (particularly those arising in the gastrointestinal tract and lungs) as well as from guidelines for other gynaecological cancers.

Types and classification

Gynaecological neuroendocrine cancers are broadly classified by their grade, or how quickly the tumour cells are dividing and how abnormal they appear under the microscope.

Low-grade neuroendocrine tumours (NETs)

Also referred to as well-differentiated NETs, these low-grade gynaecological neuroendocrine tumours grow more slowly and are generally associated with a more favourable prognosis. They are more commonly seen in the ovary than in the uterus.

Ovarian neuroendocrine tumours are often linked to mature teratomas (also called dermoid cysts), which are a type of benign ovarian cyst. In some cases, the neuroendocrine tumour develops within the teratoma.This association is unique to ovarian neuroendocrine tumours and is an important feature in diagnosis.

High-grade neuroendocrine carcinomas (NECs)

High-grade neuroendocrine carcinomas are poorly differentiated and aggressive. They grow quickly, spread early, and require prompt treatment. High-grade disease is further classified into:

• Small cell neuroendocrine carcinoma (SCNEC): behaves similarly to small cell carcinoma of the lung and is treated with platinum-based chemotherapy regimens
• Large cell neuroendocrine carcinoma (LCNEC): also highly aggressive, requiring intensive systemic treatment

High-grade neuroendocrine carcinomas of the endometrium frequently occur alongside conventional endometrial adenocarcinoma, creating a mixed tumour that can make pathological diagnosis more complex.

Primary versus metastatic disease

A critical step in diagnosing gynaecological neuroendocrine cancer is determining whether the tumour is primary (meaning it started in the ovary or uterus) or whether it represents spread from a neuroendocrine tumour elsewhere in the body.

Neuroendocrine cancers arising in the gastrointestinal tract (particularly the small intestine) or lungs can spread to the ovaries and can closely resemble primary ovarian neuroendocrine cancers on imaging and even on biopsy.

Features that suggest a primary ovarian neuroendocrine cancer include:

• The tumour is confined to one ovary (unilateral)
• An association with a teratoma in the same ovary
• No evidence of a primary tumour elsewhere after thorough investigation

Features that suggest metastatic disease include:

• Tumours in both ovaries (bilateral)
• A known or suspected neuroendocrine tumour elsewhere in the body
• Pathological features more consistent with a GI or lung primary

This distinction is important because the treatment approach and prognosis differ significantly between primary and metastatic disease.

Ovarian neuroendocrine cancer

Primary neuroendocrine cancers of the ovary represent less than 1 per cent of all ovarian malignancies, making them among the rarest gynaecological cancers encountered in clinical practice.

Who is affected

Primary ovarian neuroendocrine cancers can occur across a wide age range. Low-grade tumours and those associated with teratomas tend to occur in younger to middle-aged women. High-grade carcinomas can affect women across a broader age spectrum.

Features of primary ovarian neuroendocrine cancers

• Almost always confined to one ovary at presentation (unilateral)
• Frequently associated with a teratoma in the same ovary
• May be discovered incidentally or after investigation of abdominal symptoms
• Bilateral involvement strongly suggests the tumour has spread from another primary site

How ovarian neuroendocrine cancers spread

Ovarian neuroendocrine cancers may spread by direct shedding of cancer cells across the lining of the abdominal cavity (peritoneal spread) or through the lymphatic system. Advanced disease can also spread to the liver.

Hormone-related complications

Approximately one third of people with ovarian neuroendocrine tumours develop carcinoid syndrome: a group of symptoms caused by excess serotonin and other hormones released by the tumour. Unlike gastrointestinal NETs, ovarian neuroendocrine tumours can cause carcinoid syndrome even without liver metastases because hormones released by ovarian NETs bypass the liver and enter the bloodstream directly.

Endometrial neuroendocrine cancer

Neuroendocrine cancer of the endometrium develop in the inner lining of the uterus and are even rarer than ovarian neuroendocrine cancers. They are predominantly high-grade (poorly differentiated) and behave aggressively.

Who is affected

Endometrial neuroendocrine cancer most commonly affect postmenopausal women. They are sometimes detected during investigation of abnormal postmenopausal bleeding.

Mixed tumours

A distinctive feature of endometrial neuroendocrine cancer is that they frequently occur alongside conventional endometrial adenocarcinoma within the same uterus. This mixed composition can make initial pathological diagnosis challenging and requires careful immunohistochemical analysis to identify the neuroendocrine component.

The neuroendocrine component, even when present as a minor part of a mixed tumour, often drives the behaviour of the cancer. Its identification therefore has important implications for treatment planning.

How endometrial neuroendocrine cancers spread

Endometrial neuroendocrine cancer tend to spread early via the bloodstream (haematogenous spread) to the liver, lungs, bones, and sometimes the brain. This early metastatic potential contributes to the challenging prognosis associated with this tumour type.

Symptoms

Symptoms of gynaecological neuroendocrine cancers are often non-specific and can resemble more common gynaecological conditions, which contributes to late diagnosis.

Ovarian neuroendocrine cancer symptoms

• Pelvic or abdominal pain or pressure
• Abdominal bloating or swelling
• Changes in bowel habits
• Unexplained weight loss
• A palpable mass in the pelvis or abdomen
• Unexpected vaginal bleeding in postmenopausal women

Endometrial neuroendocrine cancer symptoms

• Abnormal or unexpected vaginal bleeding, particularly after menopause
• Heavy or unusual vaginal discharge
• Pelvic pain or pressure
• Abdominal discomfort

Carcinoid syndrome symptoms

When a neuroendocrine tumour produces hormones in excess (particularly serotonin) a person may develop carcinoid syndrome. For many neuroendocrine cancers, this is more common when the cancer has spread to the liver. However, ovarian neuroendocrine tumours can cause carcinoid syndrome even without liver metastases because they release these substances directly into the bloodstream.

Symptoms of carcinoid syndrome include:

• Episodic facial flushing or redness
• Persistent or watery diarrhoea
• Abdominal cramping
• Wheezing or shortness of breath
• Rapid heartbeat

Carcinoid syndrome is more often seen with low-grade (well-differentiated) ovarian neuroendocrine tumours and is rare with high-grade endometrial neuroendocrine carcinomas.

Carcinoid heart disease

In people with longstanding or uncontrolled carcinoid syndrome, prolonged exposure to high levels of serotonin can damage the heart valves, a condition called carcinoid heart disease .

Carcinoid heart disease predominantly affects the right side of the heart, causing the tricuspid and pulmonary valves to thicken and stiffen. This can lead to right heart failure over time.

People with functional gynaecological neuroendocrine tumours and symptoms of carcinoid syndrome should be assessed for carcinoid heart disease with an echocardiogram. Management of carcinoid heart disease requires specialist cardiology input alongside oncology care.

Diagnosis

Diagnosing gynaecological neuroendocrine cancers requires a combination of imaging, tissue biopsy, and specialised pathological analysis. Due to the rarity of these cancers, review by a multidisciplinary team with neuroendocrine and gynaecological oncology expertise is important.

1. Imaging

Initial investigation may include:

• Transvaginal and pelvic ultrasound
• Pelvic MRI (to assess the primary tumour and local spread)
• CT scan of the chest, abdomen, and pelvis (to assess for spread)

2. Functional imaging

Functional nuclear medicine scans are used to identify whether the tumour expresses somatostatin receptors and to map the full extent of disease throughout the body.

• Ga-68 DOTATATE PET/CT: the preferred scan for well-differentiated, low-grade neuroendocrine tumours in Australia
• FDG PET/CT: may be more appropriate for high-grade, poorly differentiated neuroendocrine carcinomas
• Octreotide scan (somatostatin receptor scintigraphy): used in selected cases where PET imaging is unavailable.

3. Biopsy and pathology

A tissue biopsy is essential for confirming the diagnosis and identifying the specific type of neuroendocrine cancer. The pathologist examines the tumour under the microscope and tests for neuroendocrine markers using a technique called immunohistochemistry.

Key neuroendocrine markers tested include:

• Chromogranin A (CgA)
• Synaptophysin
• CD56

The Ki-67 index and mitotic count are used to determine the tumour grade.

In endometrial tumours, pathological assessment also involves identifying the proportion of the tumour that is neuroendocrine versus other types of cancer cells, as mixed tumours require both components to be characterised.

4. Blood tests

Blood tests may be used to detect elevated levels of tumour markers and to assess hormonal activity:

• Chromogranin A
• 5-HIAA (urinary or plasma) recommended at diagnosis for all patients with ovarian NETs, regardless of stage or symptoms.
• Other hormone or peptide markers as clinically indicated

5. Molecular profiling

For endometrial neuroendocrine cancers in particular, molecular profiling is increasingly important in guiding treatment decisions. This may include:

• Mismatch repair (MMR) status: tumours that are mismatch repair-deficient (dMMR) may be candidates for immunotherapy
• Other molecular markers as recommended by the multidisciplinary team

An important diagnostic distinction: SCNEC versus SCCOHT

One of the most clinically significant pitfalls in the diagnosis of ovarian small cell cancers is the distinction between two entities with similar names but completely different biology and treatment:

Small cell neuroendocrine carcinoma (SCNEC) – pulmonary type

This is a true neuroendocrine cancer. It behaves like small cell carcinoma of the lung, tests positive for neuroendocrine markers on immunohistochemistry, and is treated with platinum-based chemotherapy, often combined with radiotherapy. It can affect women across a range of ages.

Small cell carcinoma of the ovary – hypercalcaemic type (SCCOHT)

Despite its name, SCCOHT is not a neuroendocrine cancer. It is a rare, aggressive ovarian cancer caused by mutations in the SMARCA4 gene. It primarily affects young women, with an average age of diagnosis of approximately 24 years, and is frequently associated with dangerously elevated blood calcium levels (hypercalcaemia).

SCCOHT does not express neuroendocrine markers on immunohistochemistry and is managed with a different treatment approach, which may include multi-agent chemotherapy, surgery, and in some cases autologous stem cell transplantation.

Accurate pathological distinction between these two conditions is essential, as they require fundamentally different treatments.

Staging

Gynaecological neuroendocrine cancers are staged using the FIGO (International Federation of Gynaecology and Obstetrics) staging system, which is used for gynaecological cancers generally.

Staging describes the extent of the primary tumour, involvement of regional lymph nodes, and presence of distant metastases. Stage at diagnosis is one of the key factors influencing treatment planning and prognosis.

Treatment options

Treatment depends on the tumour type (ovarian vs. endometrial), grade, stage, whether it is a primary or metastatic tumour, and the overall health of the person.

A multidisciplinary team may include a gynaecological oncologist, medical oncologist, radiation oncologist, nuclear medicine specialist, pathologist, radiologist, and NET nurse.

Because of the rarity of gynaecological neuroendocrine cancers, treatment is often guided by evidence from neuroendocrine cancers at other sites (particularly gastrointestinal and lung) as well as from gynaecological cancer guidelines.

Surgery

Surgery is the primary treatment for localised or resectable disease. For ovarian neuroendocrine cancers, this typically involves removal of the affected ovary and surrounding tissue, with surgical staging to assess lymph nodes and the peritoneal cavity.

For endometrial neuroendocrine cancers, surgical treatment follows the approach for endometrial cancer, including hysterectomy and lymph node assessment.

In advanced disease, surgical debulking (removing as much visible tumour as possible) may be performed to improve the effectiveness of subsequent systemic treatment and to relieve symptoms.

Chemotherapy

Platinum-based chemotherapy regimens are the standard systemic treatment for high-grade (poorly differentiated) neuroendocrine cancers of the ovary and endometrium, consistent with the approach used for small cell lung cancer and high-grade neuroendocrine carcinomas at other sites.

For mixed endometrial tumours, the neuroendocrine component typically drives chemotherapy selection.

Somatostatin analogues

For people with well-differentiated, low-grade ovarian neuroendocrine tumours (particularly those with functional tumours positive on Ga-68 DOTATATE PET/CT) somatostatin analogues such as octreotide or lanreotide may be used to:

• Control carcinoid syndrome symptoms
• Slow tumour growth in selected cases

Peptide receptor radionuclide therapy (PRRT)

PRRT may be considered for people with well-differentiated neuroendocrine tumours that express somatostatin receptors on functional imaging, when the disease has progressed or is not suitable for surgery. Eligibility depends on tumour characteristics, receptor status, and specialist assessment.

Radiotherapy

External beam radiotherapy may be considered in selected cases, particularly for endometrial neuroendocrine carcinoma as part of combined-modality treatment, or for palliation of symptomatic metastatic disease.

Emerging and targeted therapies

For advanced or recurrent disease, emerging therapies are being evaluated:

• Immunotherapy: immune checkpoint inhibitors (including those targeting the PD-1/PD-L1 pathway) are being studied for high-grade gynaecological neuroendocrine carcinomas, particularly in tumours with mismatch repair deficiency (dMMR)
• Angiogenesis inhibitors: agents such as bevacizumab are being investigated in combination with chemotherapy, given the high vascularity of neuroendocrine carcinomas
• Other targeted therapies: based on molecular profiling results and specialist recommendation

Given the rarity of these cancers, participation in clinical trials may be an important consideration for people with advanced or treatment-resistant disease.

Living with gynaecological neuroendocrine cancer

A diagnosis of gynaecological neuroendocrine cancer can be deeply confronting, particularly because these cancers are rare, are often found at an advanced stage, and may carry an uncertain prognosis.

For women with low-grade ovarian neuroendocrine tumours, outcomes are often more favourable and the focus shifts to ongoing surveillance, symptom management, and quality of life.

For those with high-grade disease, treatment is intensive and the journey often involves significant physical, emotional, and practical challenges.

Common concerns include:

• Understanding a rare and complex pathology report
• Navigating treatment decisions in the absence of disease-specific guidelines
• Managing the symptoms of carcinoid syndrome
• Addressing the impact of treatment on fertility (particularly for younger women)
• Emotional support through a rare cancer experience

Many women find that connecting with a specialist team that has neuroendocrine cancer expertise, alongside gynaecological oncology, makes a meaningful difference in their care.

Fertility considerations

For women of reproductive age diagnosed with gynaecological neuroendocrine cancer, the impact of treatment on fertility is an important consideration.

Depending on the stage, grade, and location of the tumour, fertility-sparing approaches may sometimes be possible for carefully selected low-grade, early-stage ovarian neuroendocrine tumours. This should be discussed with the treating team before any surgery or treatment is initiated.

For women with high-grade or advanced disease, treatment priorities and fertility preservation options should be explored with the multidisciplinary team and a fertility specialist as early as possible.

Follow-up and surveillance

Follow-up after treatment for gynaecological neuroendocrine cancer depends on the tumour grade, stage, type of treatment received, and whether the disease was primary or metastatic.

Surveillance typically includes:

• Physical and gynaecological examination
• Chromogranin A and other blood markers
• 5-HIAA testing if carcinoid syndrome was present
• CT or MRI imaging
• Ga-68 DOTATATE PET/CT or FDG PET/CT where appropriate
• Echocardiogram to monitor for carcinoid heart disease in people with functional tumours
• Monitoring for treatment-related side effects

Research and future directions

Research into gynaecological neuroendocrine cancers is limited by their rarity, but important progress is being made through international collaborations and case series.

Key areas of research include:

• Better characterisation of primary gynaecological neuroendocrine cancers through molecular profiling
• Understanding the role of immunotherapy in dMMR and high tumour mutational burden gynaecological NECs
• Developing disease-specific clinical guidelines from pooled international data
• Improving differentiation betweenSCNEC from SCCOHT through molecular and immunohistochemical markers
• The role of PRRT in somatostatin receptor-positive gynaecological NETs
• Improving outcomes for endometrial neuroendocrine carcinoma, particularly with regard to systemic therapy
• Exploring fertility-sparing approaches for selected low-grade tumours

Clinical trials may be available through specialist centres for people with advanced or recurrent disease.

Support available through NeuroEndocrine Cancer Australia

A diagnosis of gynaecological neuroendocrine cancer can feel isolating because these cancers are so rare and so few people have direct experience of them. NeuroEndocrine Cancer Australia provides support for people affected by ovarian and endometrial neuroendocrine cancer and their families, including:

• Access to the NET Nurse service
• Specialist NET dietitian and counsellor
• Patient and carer information and resources
• Support for navigating rare cancer care
• Education about neuroendocrine cancer and related treatments
• Guidance on questions to ask the treating team
• Connection to specialist information and support pathways

For support, information, and guidance after a gynaecological neuroendocrine cancer diagnosis, contact NeuroEndocrine Cancer Australia.

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