Testicular Neuroendocrine Cancer

Overview

Testicular neuroendocrine cancer, also called a testicular neuroendocrine tumour (TNET) or, historically, a testicular carcinoid tumour, is a rare type of cancer that develops from neuroendocrine cells within the testicle. TNETs account for less than 1 per cent of all testicular neoplasms.

Although neuroendocrine tumours most commonly arise in the gastrointestinal tract and lungs, their occurrence in the testicles is unusual and their behaviour differs from the more common germ cell testicular cancers such as seminoma and non-seminoma. In particular, the standard tumour markers used to support diagnosis and monitor common testicular cancers are typically normal in TNETs, and a different diagnostic pathway is required.

Most testicular NETs are well-differentiated, slow-growing tumours with a generally favourable prognosis when detected and treated early. However, neuroendocrine tumours can also spread to the testes from a primary tumour elsewhere in the body. Therefore, determining whether a testicular NET is primary or secondary is a critical part of the diagnostic workup.

At NeuroEndocrine Cancer Australia (NECA), our mission is to support patients and families affected by neuroendocrine cancers, including testicular neuroendocrine cancer. We offer resources, educational materials, and advocacy to improve understanding and care. For support after a testicular neuroendocrine cancer diagnosis, contact our NET Nurse, Counsellor and Dietitian services.

Understanding testicular neuroendocrine cancer

The testicles are part of the male reproductive system and produce sperm and testosterone. Like other organs, the testicles contain small numbers of specialised neuroendocrine cells that help regulate hormone release and local tissue responses.

Testicular neuroendocrine cancers arise from these neuroendocrine cells and are classified into three subtypes based on their origin.

Primary testicular neuroendocrine cancers develop directly within the testicle itself without association with other tumour elements. These account for the majority of cases and are typically well-differentiated, slow-growing tumours.

Secondary testicular neuroendocrine cancers are metastases from a neuroendocrine primary tumour that started elsewhere in the body, most commonly in the small bowel, lung, or another gastrointestinal site. Secondary TNETs are particularly important to identify because they indicate advanced metastatic disease from the primary site and carry a different prognosis and management approach.

Testicular neuroendocrine cancers associated with teratoma occur alongside a teratoma, which is a type of germ cell tumour. In these cases, the neuroendocrine tumour develops within or alongside the teratoma as part of the complex mixture of tissues that can be present in a teratoma.

Under the microscope, well-differentiated testicular NETs display features typical of neuroendocrine tumours elsewhere in the body, including a characteristic “salt and pepper” pattern of nuclear chromatin and organised insular growth patterns. These features help pathologists confirm the neuroendocrine origin of the tumour.

Causes of testicular neuroendocrine cancer

The exact cause of testicular neuroendocrine cancer is not well understood. Primary testicular neuroendocrine cancers are almost always sporadic, occurring by chance without a clear inherited cause or known risk factor.

Unlike some gastrointestinal or pancreatic neuroendocrine cancers, which can be associated with inherited syndromes such as Multiple Endocrine Neoplasia type 1 (MEN1) or Von Hippel-Lindau (VHL) disease, primary testicular NETs are not typically linked to these hereditary conditions. Genetic counselling is not routinely required unless there are other features suggestive of an inherited syndrome.

Secondary testicular NETs result from spread of a primary neuroendocrine cancer originating elsewhere in the body. In these cases, understanding the cause relates to the primary tumour site rather than the testicular location.

Testicular neuroendocrine cancers occur across a wide age range, with a median age at diagnosis of approximately 39 years, though cases have been reported in younger adolescents and older adults. They can develop in anyone with testicular tissue.

Effects of testicular neuroendocrine cancer on the body

The effects of testicular neuroendocrine cancer on the body depend primarily on whether the tumour is primary or secondary, its size and grade, and whether it produces hormones.

Most primary testicular NETs are non-functioning or produce insufficient hormones to cause systemic effects. The main local effect is a mass within the testicle, which may cause a sense of heaviness or altered sensation.

In a subset of cases, particularly when the tumour is functional and has spread to the liver, serotonin and other substances released into the bloodstream can cause carcinoid syndrome. This includes flushing, diarrhoea, and wheezing. Carcinoid syndrome is uncommon in primary testicular NETs and, when it does occur, usually indicates metastatic disease with liver involvement.

Secondary testicular neuroendocrine cancers reflect systemic disease from a primary tumour elsewhere. In these cases, symptoms and treatment considerations are usually determined by the original tumour site and the overall extent of disease, rather than the testicular involvement alone.

In rare cases, excess hormone production by a testicular neuroendocrine cancer may cause changes in hormone balance, which may lead to enlargement of breast tissue (gynaecomastia). This occurs when the balance between oestrogen and testosterone activity is disrupted.

Symptoms of testicular neuroendocrine cancer

Early-stage testicular neuroendocrine cancers are often asymptomatic and may be found incidentally during examination or imaging performed for another reason.

When symptoms do occur, they typically relate to the local effects of the testicular mass and may include:

• A painless, firm lump or swelling in one testicle
• A dull ache, dragging sensation, or feeling of heaviness in the scrotum
• A change in the size or feel of one testicle
• Mild discomfort in the groin or lower abdomen

Systemic symptoms that may suggest carcinoid syndrome include:

• Flushing of the face and neck
• Persistent or watery diarrhoea
• Wheezing or shortness of breath

These systemic symptoms are uncommon in primary testicular neuroendocrine cancers and, when present, warrant thorough evaluation for metastatic disease.

Gynaecomastia (enlargement or tenderness of breast tissue) can occasionally occur due to disruption of the normal balance between hormones, particularly oestrogen and testosterone.

Any new testicular lump or change should be assessed by a doctor promptly, as early evaluation is important regardless of the underlying cause.

Diagnosis of testicular neuroendocrine cancer

Diagnosing testicular neuroendocrine cancer requires a combination of clinical assessment, imaging, biochemical testing, and pathological examination. Because standard testicular tumour markers are usually normal in TNETs, a specialist diagnostic approach is needed.

1. Clinical examination and scrotal ultrasound

A testicular ultrasound is typically the first investigation when a testicular mass is identified. It provides detailed information about the size, location, and characteristics of the mass and can help distinguish it from other testicular conditions.

2. Standard tumour marker testing

Although standard testicular tumour markers including alpha-fetoprotein (AFP), beta-human chorionic gonadotrophin (beta-hCG), and lactate dehydrogenase (LDH) are routinely measured when any testicular mass is identified, these markers are typically normal in pure primary testicular neuroendocrine cancers. This is an important distinction from common germ cell testicular cancers, where these markers are frequently elevated.

3. Neuroendocrine-specific biochemical testing

If a neuroendocrine cancer is suspected, specialised biochemical tests are ordered:

• Chromogranin A (CgA): a blood marker elevated in many neuroendocrine tumours, used to help assess disease extent and monitor response to treatment
• 24-hour urinary 5-HIAA: measures a breakdown product of serotonin in the urine. It is mainly used when a tumour is suspected to be producing serotonin, such as in people with carcinoid syndrome.

These tests help assess whether the tumour is producing hormones and can provide information about tumour burden.

4. Tumour grading

Once tissue is available from surgical removal, the tumour is graded based on differentiation and the Ki-67 proliferation index:

• Grade 1 (G1): well-differentiated, Ki-67 below 3 per cent. Slow-growing with low risk of spread.
• Grade 2 (G2): well-differentiated, Ki-67 between 3 and 20 per cent. Intermediate growth rate.
• Grade 3 NET (G3 NET): well-differentiated but rapidly dividing, Ki-67 above 20 per cent.
• Grade 3 Neuroendocrine Carcinoma (NEC): poorly differentiated, highly aggressive.

Immunohistochemical markers including Chromogranin A, Synaptophysin, and CD56 confirm neuroendocrine origin.

5. Imaging to exclude secondary disease

Before a testicular neuroendocrine cancer can be classified as primary, it is essential to exclude the possibility that it represents metastatic disease from a neuroendocrine cancer originating elsewhere. This typically involves cross-sectional imaging, contrast-enhanced CT scanning of the chest, abdomen, and pelvis.

For well-differentiated tumours, Gallium-68 DOTATATE PET/CT provides functional imaging of somatostatin receptor-expressing neuroendocrine cells throughout the body. This scan is particularly useful in identifying a primary tumour that may have spread to the testicle.

6. Surgical pathology

Because of the risk of disrupting lymphatic drainage pathways and potentially affecting patterns of tumour spread, biopsy through the scrotal skin is generally avoided when a testicular malignancy is suspected. Diagnosis is usually made through pathological examination of the testis after radical inguinal orchidectomy, where the testis is removed through an incision in the groin. The pathology assessment helps determine the tumour type, grade, and whether it represents a primary or metastatic disease.

Treatment options for testicular neuroendocrine cancer

Treatment depends on whether the testicular neuroendocrine cancer is primary or secondary, tumour grade, size, and whether it has spread. A specialist multidisciplinary team including a urologist, medical oncologist, nuclear medicine specialist, and pathologist should guide treatment planning.

Radical inguinal orchidectomy

Radical inguinal orchidectomy, the surgical removal of the affected testicle and spermatic cord through an incision in the groin, is the primary treatment for localised testicular neuroendocrine tumours. The inguinal approach is specifically chosen rather than a scrotal incision because it preserves normal lymphatic drainage pathways and reduces the risk of tumour spread.

For primary localised TNETs, orchidectomy is often curative and is both the definitive treatment and the means by which definitive diagnosis is confirmed.

Retroperitoneal lymph node dissection

If imaging reveals spread to the retroperitoneal lymph nodes behind the abdomen, a retroperitoneal lymph node dissection (RPLND) may be performed. This involves removing the affected lymph nodes in the retroperitoneal space and is typically offered when nodal disease is identified.

Somatostatin analogues

For patients with carcinoid syndrome or those with advanced well-differentiated TNETs, somatostatin analogues such as octreotide or lanreotide can help control hormone-related symptoms and slow tumour growth.

Peptide receptor radionuclide therapy (PRRT)

For advanced, inoperable, or metastatic well-differentiated TNETs that express somatostatin receptors on functional imaging, PRRT may be considered. PRRT delivers targeted radiation to neuroendocrine tumour cells by coupling a radioactive molecule to a somatostatin analogue..

Chemotherapy and targeted therapies

For poorly differentiated neuroendocrine carcinomas (NECs), systemic chemotherapy is the primary treatment approach. Platinum-based regimens are typically used for high-grade poorly differentiated disease.

For advanced well-differentiated higher-grade TNETs, targeted therapies including everolimus may be considered in selected cases. Treatment decisions for advanced disease should be guided by a specialist multidisciplinary team with experience in neuroendocrine cancers.

Management of secondary testicular NETs

When a testicular neuroendocrine cancer represents metastatic disease, treatment is guided by the site where the tumour first developed and the extent of the disease. Orchidectomy may still be performed to confirm diagnosis and achieve local control of the testicular lesion. Systemic treatment follows the approach appropriate for the primary tumour site.

Living with testicular neuroendocrine cancer

For most people with primary localised testicular neuroendocrine cancer treated with orchidectomy, the outlook is favourable and many people return to normal daily life after recovery from surgery. However, testicular neuroendocrine cancer requires ongoing follow-up because these tumours can grow slowly and, in a small proportion of cases, recur or spread years after the original diagnosis.

The diagnosis and treatment of testicular cancer can have a significant impact on physical and emotional wellbeing, body image, and concerns about fertility and sexuality. These are legitimate and important aspects of care that deserve attention alongside medical management. NeuroEndocrine Cancer Australia provides access to a specialist NET counsellor as part of its support services.

For men with one testicle remaining after orchidectomy, testosterone production and fertility are usually maintained, though this varies between individuals. Anyone with concerns about hormonal effects, fertility, or sexual function after orchidectomy should discuss these with their treating team, who can refer to appropriate specialist services.

Dietary considerations

There are no specific dietary restrictions associated with testicular neuroendocrine cancer in general. For those with carcinoid syndrome or those on long-term somatostatin analogues, specific dietary adjustments may help manage symptoms such as diarrhoea and flushing. A dietitian with experience in neuroendocrine cancer can provide individual guidance.

NeuroEndocrine Cancer Australia provides access to a specialist NET dietitian as part of its support services.

Monitoring symptoms

After treatment for testicular neuroendocrine cancer, it is important to monitor for any signs of recurrence or progression. Symptoms to report promptly include new lumps or swelling, unexplained changes in the remaining testicle, flank pain, unexplained weight loss, and any features of carcinoid syndrome such as flushing or diarrhoea.

The risk of recurrence depends on factors such as tumour size, grade, stage, and individual tumour characteristics. Long-term surveillance is therefore an essential part of care even when the initial outcome appears excellent.

Supportive care and resources

A diagnosis of testicular neuroendocrine cancer can raise significant concerns about masculinity, body image, fertility, and the future. Psychological support, peer connection, and access to accurate information are all important parts of comprehensive care.

NeuroEndocrine Cancer Australia provides education, resources, advocacy, and access to specialist services for people affected by testicular neuroendocrine cancer and their families, including the NET Nurse service and specialist NET counsellor and dietitian.

Research and future directions

Research into testicular neuroendocrine cancer is limited by its rarity, with most knowledge derived from case series and case reports rather than large clinical trials. However, advances in the broader field of neuroendocrine cancer science continue to improve understanding and treatment.

Ongoing studies and clinical trials

Clinical trials investigating novel treatments for advanced and metastatic neuroendocrine tumours, including new targeted therapies, refined PRRT delivery methods, and immunotherapy approaches, may be relevant to people with advanced testicular neuroendocrine cancer. Australia participates in international clinical trial networks for neuroendocrine cancers.

People with advanced or treatment-resistant testicular neuroendocrine cancer should speak with their treating team about whether any currently open clinical trials may be appropriate.

Potential breakthroughs in testicular neuroendocrine cancer management

Future directions include improved molecular profiling to better predict which primary testicular neuroendocrine cancers carry a higher risk of recurrence or spread, more refined surveillance strategies for long-term follow-up, and broader access to systemic therapies such as PRRT for those with advanced disease. Better characterisation of the molecular features of testicular NETs may also clarify their relationship to other neuroendocrine tumour types and open new therapeutic possibilities.

As the broader evidence base for neuroendocrine tumour management grows, the benefits of advances in functional imaging, targeted therapies, and personalised treatment approaches will increasingly extend to people with testicular NETs.

Testicular neuroendocrine cancer is among the rarest forms of neuroendocrine cancer. While primary localised tumours generally carry a favourable prognosis with appropriate treatment, thorough investigation to exclude secondary disease, correct surgical technique, and long-term surveillance are essential to achieving the best possible outcome.

For patients diagnosed with testicular neuroendocrine cancer, contact NeuroEndocrine Cancer Australia for comprehensive support and information through our NET Nurse service.