The Heterogeneity of Grade 3 (High grade) Neuroendocrine Neoplasms

High Grade – the forgotten patient group?

When reading articles in the mainstream media, found in medical publications; and even listening to doctors speak about my disease, it’s clear that the focus is on the term “Neuroendocrine Tumours” or NET for short.  Many websites of advocate foundation organisations and specialist scientific organisations, all still use the term “NET” in their naming.  I too am guilty of having a large Facebook site falling into this category.  It’s little wonder that those with high grade disease can often feel like the forgotten patient group.  Clearly all the aforementioned organisations support all patients regardless of grade, but it’s true to say that the naming and general use of terminology continues to fall behind. It’s also true that the term NET remains applicable to the majority of patients and that many use it as a convenience when they actually mean all types including Neuroendocrine Carcinoma. Nonetheless, context remains an important part of overall understanding and inclusivity – words and acronyms matter.

However, High grade or Grade 3 is no longer just Neuroendocrine Carcinoma (NEC).  Things have changed since 2017 and have been reinforced in 2019.

What are Neuroendocrine Neoplasms?

Neuroendocrine neoplasms (NENs) are without doubt a heterogeneous (i.e. diverse) bunch of tumours with a common phenotype (i.e. the physical appearance or biochemical characteristic).  However, there are two fundamentally different groups of NENs: well-differentiated, low-proliferating NENs, called neuroendocrine tumours (NETs), and poorly differentiated, highly proliferating NENs, called neuroendocrine carcinomas (NECs).  The difference between well and poorly differentiated has been described as a ‘dichotomy’, most likely due to the origin from different neuroendocrine progenitor cells (i.e. source cells). Should the term Neuroendocrine Neoplasm be used more?  Yes, probably. But should we perhaps also ask if ENETS and NANETS will change their names to ENENS and NANENS?

This revised classification is not recent as many are currently suggesting.  These changes were covered in my Staging and Grading article produced in early 2017 and confirmed Neuroendocrine Neoplasms (or NENs) was the overarching term for all types of neuroendocrine disease.  See graphic below, recently updated to incorporate 2019 updates.

Traditionally, any proliferation score over 20% on the Ki-67 proliferation index (or over 20 mitoses/10 HPF on the Mitotic Index) would have been deemed a Neuroendocrine Carcinoma.  However, in the pancreas, NETs and NECs may overlap in their proliferation index, making the distinction between them difficult and leading to treatment uncertainties.

In 2017, the Endocrine ‘Blue Book’ of cancer classification systems introduced a new pancreatic NET category based on a Grade 3 tumour which is well differentiated (i.e. cancer cells look more like normal cells and tend to grow and spread more slowly).  While all classifications for all NENs recognise the existence of the two major groups (NET and NEC), there are proposals to develop common NEN classification across all the ‘Blue Books’ and future versions will reflect these changes. The most interesting change will be in the Lung classification because high grade NENs can be small cell or large cell and it’s probably the most controversial grouping.

Interestingly, ENETS guidelines already use the term across the board in their 2016 series (i.e. in advance of the 2017 changes).  These changes are part influenced by the results of the NORDIC NEC study which showed that although patients with a Ki67 <55% were less responsive to platinum-based chemotherapy (i.e. drug names ending in ‘platin’ such as Cisplatin, Carboplatin, Oxaliplatin), they had a longer survival, and concluded that not all NEC should be considered as one single disease entity.  Also worth noting that the NORDIC NEC study covered many different areas of the anatomy, not just the pancreas. Some of the rationale for the division of grade 3 into well differentiated NETs and poorly differentiated carcinomas is that some grade 3 tumours which are classified into this category according to the Ki67 index percentage, have been recognised to behave more like grade 2 NETs rather than aggressive carcinomas. The inference is that there could be treatment and prognostic significance (advantages) if a patient is a Grade 3 NET.

These changes were reinforced in the 2019 updateread here



Added for completeness because most of these mixed cell tumoursinvolve a Grade 3 NEN. This mixed and rare neoplasm type has traditionally been related to NEC but in 2017 the nomenclature change to a new term was necessary to reflect the fact that some of the tumours involved were not carcinomas or adenocarcinomas but rather were well differentiated tumours or even adenomas (i.e. benign). Previously known as Mixed AdenoNeuroendocrine Carcinoma (MANEC), they were renamed to Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).

MiNEN are neoplasms with two distinct neuroendocrine and non-neuroendocrine cell populations. They can be morphologically classified into three entities: collision, composite, and amphicrine MiNEN. Currently, both components composing a MiNEN must represent at least 30% of the whole tumour.  Diagnosis of MiNEN is usually facilitated by the presence of at least one well-differentiated component which may be the Neuroendocrine or Non-Neuroendocrine component. However, the two components may be difficult to identify with conventional morphological techniques, particularly when they are poorly differentiated, and their identification may require additional immunohistochemical techniques. MiNEN usually originate from organs that contain neuroendocrine cells and in which “classical” NENs are known to develop, such as pancreas, appendix, colon, and to a lesser degree small intestine. Other locations in my source document includes Oesophagus, Stomach, Bilary Tract and Gallbladder, Duodenum and Ampulla of Vater and Rectum.

Molecular signatures

One of the study areas which will help with accurate diagnoses of well or poorly differentiated NENs is the use of molecular signatures. This is an advancing science and something which may also be utilised in other areas of NENs. The abstract below is extremely interesting which will help experts update guidelines to include pathology checks on the genetic abnormalities in the TP53 and Rb1 genes in cases of G3 NENs.  This study also supports the key differences in terms of the more common locations of G3 NET vs the more common locations of NEC. 

Kasajima, A., Konukiewitz, B., Schlitter, A.M. et al. An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features. Virchows Arch (2021).

“Limited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN). We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.”


Having researched widely, I believe there are 8 key differences between NET and NEC:

      1. Grade – NEC is by default Grade 3/high grade so there is no requirement to use either term – Neuroendocrine Carcinoma suffices, NETs however, can be Grade 1, 2 or 3.
      2. Differentiation – all NETs are well differentiated by default, NECs are poorly differentiated by default.  Important difference when the Ki67/Mitotic Count indicates Grade 3.
      3. Aggressiveness – Most NETs tend to be indolent or slow growing while NECs tend to be aggressive and faster growing. However, Ki67 and/or mitotic count is an aggressiveness measurement tool.  Genetic profiles can also be a guide but this is beyond the purposes of this article but may be explored in subsequent parts.  It follows that NECs normally have a worse prognosis in comparison to NETs.
      4. Hormone Secretion – NETs can produce peptide hormones that may be associated with hormonal syndromes.  NECs usually fail to express hormones or produce hormonal syndromes.
      5. Somatostatin Receptors – A NET is much more likely to express somatostatin receptors which can influence treatments such as somatostatin analogues and peptide receptor radiotherapy (PRRT)
      6. Hereditary Syndromes – NETs are much more likely to be associated with hereditary syndromes such as Multiple Endocrine Neoplasia (MEN).
      7. Platinum Based Chemotherapy – NETs are less likely to show a good response to platinum based chemotherapy which can often be the first line treatment for NEC.
      8. Primary Locations – can be vastly different in terms of commonality and therefore provide clues to investigators. Common locations for NEC include: Lung, Esophagus, Colon, Urogential Organs and Skin –  with the exception of Lung, these are very rare locations in NETs.  Conversely, rare/very rare locations for NEC but common in NET include: Rectal, Small Intestine, Appendix, Stomach, Pancreas.

This is a start to the treatment differences between G3 NET and NEC. 

The reason treatment options are not fully tied down is due to lack of data. As more studies and trials are complete, this will start to firm up.  We are also waiting on data from PRRT trials, particularly in the case of well differentiated G3 NET. 

“Treatment Outcomes of Well‐Differentiated High‐Grade Neuroendocrine Tumors”


Recent classification of neuroendocrine neoplasms has defined well‐differentiated high‐grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well‐described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens.

Materials and Methods

This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients’ demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression‐free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR).


Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki‐67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum‐etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96–16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months.


Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short‐lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy.

Implications for Practice

High‐grade well‐differentiated neuroendocrine tumors (NET G3) are considered a different entity from low‐grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well‐differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.


It will be useful to see what changes to the above will be once we have the output from the NETTER-2 clinical trial which is focussed on Grade 2 and Grade 3 well differentiated.  And also, any decision to automatically apply molecular signature checks to all G3 NENs.

In addition to my own knowledge gained over the years of researching and writing, the following resources were key in establishing the facts used in compiling this article:

1. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al: Predictive and prognostic factors for treatment and survival
in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24: 152–160

2. de Mestier L, Cros J, Neuzillet C, Hentic O, Egal A, Muller N, Bouché O, Cadiot G, Ruszniewski P, Couvelard A, Hammel P: Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms. Neuroendocrinology 2017;105:412-425. doi: 10.1159/000475527

3. Koppel G: Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med 2017;33:324-330. doi: 10.1159/000481390

4. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–1786. doi:10.1038/s41379-018-0110-y

5. Alex J LiuBenjamin E UeberrothPatrick W McGarrahSkye A Buckner PettyAyse Tuba KendiJason Starr, Timothy J HobdayThorvardur R HalfdanarsonMohamad Bassam Sonbol – Oncologist 2021 May;26(5):383-388. doi: 10.1002/onco.13686. Epub 2021 Feb 8. 

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5 thoughts on “The Heterogeneity of Grade 3 (High grade) Neuroendocrine Neoplasms

  • Linda

    NANETS is producing new classification guide for NETS and MEN. Expected to be released January 2020

  • Joan

    Great article, Ronny! Thanks for bringing this information to the masses! Looking forward to part 2!

  • Liz

    Ronny, your blog is one of my first go-to places when I want to update myself on the latest NET therapies. I’ve just had my first Galium PET scan and will soon start PRRT. Your blog means that I’m going into treatment much better informed than if I’d randomly searched the web or tried to wade through numerous scientific articles. Thank you for doing that for me. Thank you for being there.

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