Neuroendocrine cancers are a heterogeneous group of cancers that arise from hormone-producing neuroendocrine cells. Most neuroendocrine cancers are considered well-differentiated and slow growing, often allowing patients to live for many years after diagnosis with appropriate management.
However, there are subsets of NETs and neuroendocrine carcinomas (NECs) that are considered rare or aggressive, including high-grade NECs and NETs arising in a variety of primary sites. These tumours can behave very differently from the more common well-differentiated NETs and present unique challenges for diagnosis, treatment, and prognosis.
Let’s explore what makes these tumours rare or aggressive, factors that influence their outcomes, survival expectations, treatment challenges, and the promise of emerging research to improve care.
NeuroEndocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with Neuroendocrine Cancers, and their families. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of Neuroendocrine Cancers, improving patient care, and encouraging research advancements. Patients diagnosed with neuroendocrine cancers can engage with NECA’s comprehensive support and information by calling the NET nurse line.
While neuroendocrine cancer is an umbrella term, some types are particularly rare or aggressive.
Rare neuroendocrine tumours (NETs) can arise in uncommon sites such as the thymus, kidney, ovary, breast, or skin (Merkel cell carcinoma). These locations account for only a small percentage of all NET diagnoses, but their unusual presentation often leads to delayed recognition and diagnosis.
High-grade neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs) are typically defined by rapid growth, high proliferative activity, and poor differentiation. This group includes large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCC), which may occur in the lung or other organs. These cancers tend to spread early and have a higher likelihood of recurrence, even after treatment.
Compared with well-differentiated NETs, NECs tend to have:
Rare NETs may also behave unpredictably, as there is limited research on their natural history. For example, primary renal NETs can present with haematuria or flank pain but are often discovered incidentally. Their behaviour can range from indolent to aggressive, depending on differentiation and stage.
Tumour grade remains the most powerful predictor of prognosis. Well-differentiated Grade 1 NETs can have five-year survival rates exceeding 80 per cent, while high-grade NECs are associated with median survival times of less than one year in advanced stages.
Differentiation, the degree to which tumour cells resemble normal neuroendocrine cells, also matters. Poorly differentiated NECs are far more aggressive and respond differently to treatment compared with well-differentiated tumours, even if they share the same Ki-67 index.
Stage at diagnosis significantly impacts prognosis. Localised rare NETs, when surgically resectable, may have good long-term outcomes.
However, most NETs and high-grade NECs are diagnosed at an advanced stage with around 60% of NETs diagnosed at stage 4. As a result, high-grade NETs and NECs are often detected only once the disease has spread, limiting treatment options and overall survival.
Metastatic disease, particularly with liver involvement, reduces survival considerably. The presence of distant metastases at diagnosis is associated with a higher likelihood of rapid progression and shorter progression-free survival (PFS).
Molecular profiling has revealed that aggressive NETs and NECs often harbour mutations in tumour suppressor genes such as TP53 and RB1, or alterations in DNA repair pathways. In contrast, some well-differentiated NETs can show mutations in MEN1, DAXX, or ATRX.
These differences partly explain the disparity in growth rates and treatment response. Genetic features are now being used to guide personalised therapy approaches, with clinical trials exploring targeted agents for specific mutations.
Well-differentiated gastrointestinal and pancreatic NETs often have prolonged survival, even in the presence of metastases, with median overall survival exceeding five to seven years. By contrast, small-cell NEC of the lung has a median survival of less than 18 months, even with chemotherapy and radiotherapy. Extrapulmonary NECs share a similarly poor prognosis with survival highly dependent on response to first-line platinum-based chemotherapy.
Not all aggressive neuroendocrine cancers behave the same way. For example, large-cell NECs may have a slightly better prognosis than small-cell variants when treated aggressively. Merkel cell carcinoma outcomes are highly variable but have improved in recent years with the advent of immunotherapy. Thymic NETs have a higher recurrence rate compared with thymomas and may require prolonged surveillance even after complete resection.
Because rare NETs and NECs make up such a small proportion of overall neuroendocrine cancer cases, there are limited randomised controlled trials to guide treatment. Clinicians often rely on retrospective studies, case series, or extrapolation from more common NETs. This lack of data can make it difficult to standardise care, and treatment decisions often depend on multidisciplinary team consensus.
Aggressive NECs are typically treated with platinum-based chemotherapy regimens similar to those used in small-cell lung cancer. While response rates are initially high, relapses are frequent and responses to second-line treatment are often of limited duration.
Well-differentiated but high-grade NETs can be particularly challenging, as they may not respond well to either standard NET therapies (like SSAs) or to NEC chemotherapy regimens, requiring highly individualised approaches.
Early detection offers the best chance of curative treatment for rare NETs. Identifying aggressive disease before it metastasises allows for complete surgical resection in some cases. For high-grade tumours, early initiation of chemotherapy can improve symptom control and delay progression.
Symptoms of rare NETs are often nonspecific and may mimic common conditions such as irritable bowel syndrome, asthma, or menopause. This leads to diagnostic delays.
Limited awareness among general practitioners and non-specialist clinicians also contributes to late-stage presentation. Improved education and clinical pathways are needed to shorten the time from symptom onset to diagnosis.
Research is underway to find more effective therapies for rare and aggressive NETs and NECs. Immunotherapy with PD-1 and PD-L1 inhibitors has shown promise in Merkel cell carcinoma and is being tested in other NEC subtypes.
Trials are exploring targeted therapies against specific genetic alterations, including PARP inhibitors for tumours with DNA repair deficiencies. Combination therapies, such as chemotherapy plus immune checkpoint blockade, are being evaluated to enhance response rates.
Although high-grade NECs remain challenging to treat, progress is being made. Better molecular characterisation of these tumours is helping researchers design trials that match therapies to tumour biology.
Personalised medicine approaches, including circulating tumour DNA monitoring, may allow for earlier detection of relapse and more timely treatment interventions. With continued research funding and international collaboration, the outlook for patients with rare and aggressive NETs and NECs is expected to improve over the coming decade.
Rare and aggressive neuroendocrine cancers represent some of the most challenging cases in oncology. Their rapid growth, limited evidence base, and high recurrence rates demand an individualised and multidisciplinary approach. Despite these hurdles, advances in molecular research, targeted therapies, and immunotherapy are paving the way for better outcomes.
For patients and families, early diagnosis and access to specialist NET centres of excellence remain key to improving survival and quality of life. Ongoing education for healthcare professionals and the public can help close the gap between symptom onset and treatment, ultimately giving patients with rare and aggressive NETs and NECs a better chance for meaningful survival and improved daily living.
Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line.
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