Paraneoplastic Syndromes – the NET Effect

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Although several hypotheses have been proposed regarding the pathogenesis of Paraneoplastic Syndromes (PNS), the precise mechanism that leads to the development of PNS remains largely unknown. In simple terms, pathogenesis means “the manner of development of a disease”.

Disclaimer. I read widely and noted various papers where there was clearly confusion about the classification of paraneoplastic in relation to Neuroendocrine Neoplasms.  Some papers grouped known Neuroendocrine Tumour hormonal syndromes in, but others were more specific by filtering these into ectopic scenarios.  I eventually filtered out papers based on the expertise of the authors and the common threads running in each one.  It was not easy. This is a hugely complex area.

One paper stands out and includes one of the world’s top Endocrinologists. In 2025, the European Society of Endocrinology (ESE) announce Professor Ashley Grossman, F.Med.Sci was the winner of the 2025 Transatlantic Alliance Award, which was launched in 2021, recognizes an international leader who has made significant advancements in endocrine research on both sides of the Atlantic—in the United States and Europe. He is emeritus professor of endocrinology at the University of Oxford, a senior research fellow at Green Templeton College in Oxford, U.K. and is also a professor of neuroendocrinology at Queen Mary University of London U.K.  If that wasn’t enough, he also happens to be a member of the Centre of Excellence at Royal Free London, itself one of the top NET places on the planet.  Ergo, he knows what he is talking about!  So when he says “the precise mechanism that leads to the development of PNS remains largely unknown, then that must be accurate. 

What are Paraneoplastic Syndromes (PNS)?

The term paraneoplastic syndrome (PNS) is used to define a spectrum of symptoms attributed to the production of biologically active substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells. (i.e. they are paraneoplastic in an ‘ectopic’ sense).  Worth noting these are not the same as the known hormonal syndromes related to Neuroendocrine Tumours (NETs) but you will see some overlap within the paper used as a reference for most of this research.  You will also note that the original name of the 2010 paper below was entitled Paraneoplastic Endocrine Syndromes.  The word endocrine was removed in the 2020 update.

Important to note:

Worth repeating ….. although several hypotheses have been proposed regarding the pathogenesis of PNSs, the precise mechanism that leads to the development of PNS remains largely unknown.  PNSs can precede, occur concomitantly or present at a later stage of tumour development and may complicate the patient’s clinical course, response to treatment, and impact overall prognosis. Their detection can facilitate the diagnosis of the underlying neoplasia, monitor response to treatment, detect early recurrences, and correlate with prognosis. When associated with tumours of low malignant potential, PNSs usually do not affect long-term outcome. Conversely, in cases of highly malignant tumours, endocrine PNSs can be associated with poorer survival outcomes. 

Clinical awareness and the incorporation into clinical practice of somatostatin receptor based PET scans such as the ⁶⁸Ga Dotaxxx series, and other evolving biomarkers have substantially contributed to the identification of patients harbouring such syndromes.

Incidence

It has been estimated that PNSs affect approximately 8-15% of patients suffering from malignant neoplasms, mostly involving the lung, breast, and gastrointestinal system (not just NENs). Clearly a problem bigger than NENs.  However, NENs are the type of tumours expected to exhibit the highest prevalence of PNSs due to their inherent synthetic and secretory capacity.  However, to date the prevalence of NEN-related PNSs is still obscure due the limited availability of data.

Classification of PNSs

According to the clinical manifestations, the NENs-related PNSs may be classified as:

• Humoral PNSs – in medicine humoral is something relating to the body fluids, especially with regard to immune responses involving antibodies in body fluids as distinct from cells.  There are some overlaps with the NET hormonal syndromes.  See Reference 1 for the complete list of humoral PNSs. The term ‘humoral’ is important for context.
• Neurological PNSs – problems affecting the nervous system. These mostly concern non-Neuroendocrine Neoplasms but there is a connection to Small Cell Lung Cancer, technically a type of Lung Neuroendocrine Carcinoma.  See Reference 1 for the neurological PSN list if you have SCLC or another type of Neoplasm.
• Other less common manifestations. i.e. anything not fitting into humoral or neurological.  See Reference 1.

Resources Used

I first wrote this blog using a paper published in 2010 (the source of the lead diagram and I include it for this purpose below). This was something I found in my research into the term Paraneoplastic Syndromes which has outlined some of these issues in relation to NENs.  In the 2010 version, the authors suggested that paraneoplastic endocrine syndromes are a secondary complication with certain types and certain hormones. Many of these connections are already known, such as Cushing’s syndrome, hypercalcemia, hypoglycaemia. But it can be the knock-on effects of these conditions which can potentially lead to other issues discussed. 

A further variation of the same paper was produced in 2020 contained updated information and Professor Ashley Grossman was again included in the authors list – as above he is a known expert in NENs and is an Endocrinologist.  I noted the title changed from ‘secondary’ to ‘related’ indicating.  It indicates to me that the thinking changed between 2010 and 2020. The other difference I noted was the omission of Endocrine leaving just Paraneoplastic Syndromes as a standalone statement. So when you research several sites, many talk only about Paraneoplastic Syndromes, focussed on the Neurological PNS sub-classification which is less relevant to NENs.  Consequently, they omit any connection to NEN Syndromes. Many other large and well-known US clinics take the same approach. 

The one I will refer to below is more ‘endocrine’ related covering a much wider scope.  It’s also authored by known NET Specialists who are Endocrinologists.

1. Paraneoplastic Syndromes Related to Neuroendocrine Tumors (2020)

Marina Tsoli, MD, PhD, Georgios K. Dimitriadis, Ioannis I. Androulakis, Gregory Kaltsas, M.D., FRCP, and Ashley Grossman, MD, FRCP, FMedSci. Paraneoplastic Syndromes Related to Neuroendocrine Tumours. [Updated 2020 Sep 26]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279135/

This is clearly much more appropriate when looking at Paraneoplastic syndromes from a NET context. It follows that the use of any paper just focussed on Neurological PNS is not the best research article for NET related information. The 2020 paper is essentially an update of the 2010 original used as a reference to publish this blog. Paraneoplastic syndromes secondary to neuroendocrine tumours (2010) – the original reference I used for my first blog output – Kaltsas G, Androulakis II, de Herder WW, Grossman AB. Paraneoplastic syndromes secondary to neuroendocrine tumours. Endocr Relat Cancer. 2010 Jul 28;17(3):R173-93. doi: 10.1677/ERC-10-0024. PMID: 20530594. https://pubmed.ncbi.nlm.nih.gov/20530594/

Disclaimer

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