July 2026

Neuroendocrine Cancers: Typical Carcinoids, Atypical Carcinoids, and Neuroendocrine Carcinomas

Joseph Corsini, Ph.D. and Julie Alessandra, MTE

Neuroendocrine cancers are very rare. They arise from neuroendocrine cells, which exist in many tissues including the kidneys, the lungs, the intestines, and the urogenital tract. These cells receive signals from the nervous system and then secret hormones such as gastrin, serotonin, and 5-hydroxy tryptamine. Although the neuroendocrine cells are present in many tissues, neuroendocrine cancers appear most commonly in the gastrointestinal and respiratory tracts. There are two main types of neuroendocrine cancer: well-differentiated neuroendocrine tumors (typical and atypical carcinoids) and poorly differentiated neuroendocrine carcinomas (for example small-cell lung carcinoma and large-cell lung carcinoma). The latter are more aggressive and malignant and have a poor prognosis. In recent years a less common subtype that is well differentiated but fast growing and aggressive has been identified and is now part of the classification scheme (Ucella et al 2021). As with most rare cancers, root causes are poorly understood, and for unknown reasons there has been a 6-fold increase in the incidence of the neuroendocrine carcinoid tumors in the past fifty years. Typical carcinoids are slow growing with a low Ki-67 index (the Ki-67 protein is involved with the synthesis of ribosomal RNA - it is present in high concentrations in rapidly dividing cells so is used to gauge the level of cell division in many tumors); they do however metastasize in up to twenty percent of the cases. Atypical lung carcinoids, also slow growing, metastasize in up to 70% of cases. In the absence of distant metastases, surgery usually completely eliminates the cancer.  The high grade (more aggressive and malignant) neuroendocrine tumors occur in various anatomical sites, although again mostly in the respiratory and gastrointestinal tracts, and are generally defined by a Ki-67 index over 20%. In the lung they are the large and small cell neuroendocrine tumors. In the gastrointestinal tract (most commonly pancreas, small intestine, and rectum) they are referred to as high grade neuroendocrine tumors, and are divided into three subcategories determined by both molecular profiles and the KI-67 index threshold of 55% (Alese et al 2019; Busico et al 2020).

Because these tumors are very rare, standard of care treatment modalities are not well-established. Granberg and colleagues (2023) review the standard treatments regiments, which because of their low incidence have not been well-studied with large clinical trials. Several chemotherapy regiments, including DNA damaging agents like temozolomide and capecitabine, have been shown to effect modest improvements that are more pronounced in more aggressive tumors. Historically, treatment of the carcinoids, most of which overexpress the somatostatin receptor, has employed somatostatin receptor antagonists like lanreotide and octreotide. An approach called peptide receptor radionuclide therapy using 177Lu-DOTATE (DOTATE is octreotide) has also proven effective for somatostatin positive tumors. Many emerging immunotherapies are being considered, including the PD1 and CTLA4 checkpoint blockade antibodies (reviewed in Vellani et al 2023). Interestingly, targeting of the PD-1 and the CTLA4 pathways has yielded low response rates in the carcinoid tumors but higher response rates in the neuroendocrine cell carcinomas. On other fronts, clinical studies have been conducted with a bi-specific monoclonal antibody called tidutamab to treat neuroendocrine tumors. This engineered antibody binds both CD3 on cytotoxic T cells and the somatostatin receptor (SSTR2) on tumor cells, allowing the T cell to kill the tumor cell. Note that high PD-L1 expression was observed to impede this process, leading to lowered efficacy in tumors that express high levels of PD-L1.  Another monoclonal antibody, spartalizumab, has shown early promise in thoracic neuroendocrine tumors (Yao et al 2021). Other potential targets for monoclonal antibodies or other targeted therapies include GPC-3, Delta-like ligand 3, B7-H3, EGFR, and HER2. There are also a number of clinical trials exploring highly personalized tumor specific vaccines, CAR T cell therapies, dendritic cell vaccines, and natural killer cell therapies with other cancers - these should be discussed with your oncologist prior to surgery because often times fresh tumor tissue is required for the treatment. Note that there is a condition called ‘carcinoid crisis’ that can develop when many neuroendocrine tumor cells are killed quickly causing a massive release of hormones into the bloodstream. This should be discussed with and monitored by your physician with any treatment modality, including the alternative or complementary treatments discussed below.

Data describing the effects of complementary approaches with neuroendocrine tumors is sparse. A recent John’s Hopkins mistletoe study of IV mistletoe extract (Helixor M) observed stabilization of disease in a neuroendocrine tumor patient for 15 weeks (Paller et al 2023), and mistletoe has been shown repeatedly to reduce adverse effects associated with a variety of cancer treatment regimes. Note that mistletoe is known to stimulate immune responses and that interactions with various immunotherapies are not yet completely characterized but a study suggests that mistletoe therapy improves outcomes with checkpoint blockade inhibitors targeting the PD1 pathway to treat non small-cell lung carcinoma (Schad et al 2024). Deuterium depleted water has demonstrated positive effects on outcomes with other cancers and is worth considering. Studies show extended survival time for glioblastoma, prostate, pancreatic, and breast cancer patients using a deuterium depletion protocol either during or as a follow up to standard of care treatments (Boros et al 2021; Qu et al 2024, Kovacs et al 2011; Somlyai et al 2016). Given its lack of toxicity and demonstrated positive effects on outcomes with other cancers it is worth considering, however, due to the rarity of neuroendrocrine cancers, no data exists one way or the other. Similarly, molecular hydrogen shows supportive properties with many cancers which are well documented in the medical literature (for a review see Noor et al 2023) and has a low potential for toxicity but its influence on outcomes with neuroendocrine cancers is unknown. Essential oils have been shown in clinical studies to reduce adverse effects from treatment and improve emotional outlook during treatment and recovery for a variety of cancers. In addition, purified fractions of essential oils are being studied and have been shown to reduce tumor size in at least one case (Valente et al 2024). Pre-clinical work with other cancers suggests that methylene blue and near infrared light therapies may be useful in certain situations but also have not been studied with regards to neuroendocrine tumors.

Finally, there is some evidence that sunlight improves survival outcomes with at least some cancers. Beyond the importance of producing the natural forms of vitamin D, regular exposure to natural light controls circadian rhythms that are critical for anti-cancer immune responses and provide a multitude of necessary signals, especially the melatonin and melanin pathways, for optimal body functioning. When the circadian clocks become desynchronized there is a disruption in overall energy metabolism, hormone synthesis (including vitamin D), tissue repair, and cell recycling that are important at every stage of a cancer diagnosis — from prevention through the healing processes after surgery, radiation, and chemotherapy. In addition, exposure to UV light activates NRF2 pathways (Gegotek and Skrzydlewska 2015). NRF2 is considered by some to be the master regulator of cellular redox homeostasis, increasing mitochondrial function and protecting cells against a variety of carcinogenic processes that lead to the development of cancer (Chen et al 2026).