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Reviewed and edited 16th July 2023
It’s no secret that Neuroendocrine Cancer can be difficult to diagnose. Although earlier diagnosis is improving (as reported in the SEER database report issued in 2017 and also in many other places), there is still a lot of ground to cover. There are a number of reasons why these Neoplasms are often difficult to correctly and quickly diagnose including but not limited to: – they grow silently, they often produce vague symptoms which can be mistaken for much more common illnesses, and their complexity is not fully understood.
Neuroendocrine Cancer is a heterogenous group of cancers so I may use the following terms in this post:
Neuroendocrine Neoplasm (NENs) – a combination term for both well differentiated Neuroendocrine Tumours (NETs) and Neuroendocrine Carcinomas (NECs)
I wanted to cover two different aspects of the problem of finding NENs. Firstly, in finding the primary tumour and grade so that the type of NEN can be properly established – this drives the best treatment regime. Secondly, in finding all the tumours, as this establishes the correct and most detailed staging declaration – this drives treatment plans and surveillance regimes that need to be put into place. It’s important to note that cancers are named by the primary tumour. Metastases of that primary are called by the same cancer type. So as an example, a liver metastasis (liver met) of a primary Neuroendocrine Neoplasm isn’t Liver Cancer.
In this article, I’ll discuss:
1. Cancers of Unknown Primary
2. Hunting Tumours – primary vs secondary
3. Why NEN specialist knowledge helps find tumours
4. Secondary tumours appearing in common primary locations
5. Multiple primary tumours (multicentric (same location), metasynchronous (different locations), different cancers)
6. Best ways to find tumours
7. Mixed cell tumours
8. Well differentiated NETs vs Neuroendocrine Carcinomas (i.e. NET vs NEC)
Finally, despite the title of this post, many Neuroendocrine Neoplasms can be found easily once there is sufficient clinical suspicion (which sometimes needs doctors to think outside the box). It’s also true to say that huge numbers of NENs are found incidentally, that is to say they are found when doctors are investigating something else, this happens more than contributors to patient groups and patient advocate organisations would have you believe. Sometimes it just needs a decision to image the person and then perhaps more imaging to either confirm or simply more in depth looking. A CT will find most (despite what you read in patient groups). Getting to that decision point can be troublesome for some. This post is mainly what happens from this point. What is abundantly clear is that sometimes detective skills are required to reach this point and often for some time after.
Cancers of Unknown Primary
Cancer is always named for the place where it started, called the primary site. Sometimes doctors can’t tell where a cancer may have started. When cancer is found in one or more places where it seems to have spread, but the site where it started is not known, it is called a cancer of unknown primary (CUP) or an occult primary cancer.
When you look at the ratio of all cancers, the figure for cancers of unknown primary (CUP) is quite startling. Depending on where you look the figure is around 2-10%. That doesn’t seem a lot but when you consider the amount of people diagnosed with cancer, the total figure must be staggering. Interestingly, Cancer Research UK say that 60% of CUP cases are in the over 75s. In another interesting Swedish study, doctors claimed that the rates of metastatic cases were higher with certain NETs than they were in their anatomical counterparts, reinforcing the dangerous and sneaky nature of NENs.
Despite quite advanced scanning and diagnostic testing currently in place, and the extensive knowledge of NEN specialists, there can still be reasons for not being able to find the primary tumour:
- The primary is just too small to be seen and is growing quite slow. Very small cancers might not cause symptoms or be seen on scans. This is a particularly relevant point to NETs.
- The primary could be hidden in tissue in between different organs causing confusion about the actual primary location.
- The body’s immune system killed the primary tumour. It’s also possible (but not common) that any secondary cancer (i.e. metastases) are still growing.
- The tumour has become loose from its primary location and exited the body, e.g. from a wall of the bowel and excreted out in the stool.
- The primary cancer was removed during surgery for another condition and doctors didn’t know cancer had formed. For example, a uterus with cancer may be removed during a hysterectomy to treat a serious infection.
There’s an interesting study here looking at DNA methylation-based profiling to help locate the primary in Neuroendocrine Cancer – click here to read more.
Eventually, there will be accurate molecular profiling available which will close the gap on these issues.
Hunting Tumours – Primary vs Secondary
It’s really important to determine which tumours are primary and which are secondary (metastasis). There’s a number of ways to help work this out and knowledge of NENs epidemiology studies can help. The issue is complicated as well-known primary NEN locations can also be secondary (metastasis) locations.
Specialist Knowledge – certain things are known about the behaviour of NENs
Specialists and in particular NEN specialists will be aware of the vagaries of NENs in terms of what tumours are normally a primary and which are normally secondary and many of the pitfalls involved in working that out. Many NENs will have metastasized to the liver at diagnosis, so whilst it is not impossible to have a primary liver NEN, the vast majority of liver tumours found will be secondary (metastases). NEN Specialists are more likely to have the experience than generalists. They know that the varying metastatic potential depending on the primary site clearly indicates differing biology and genetics across sites and they know that NENs are indeed a heterogeneous group of tumours.
Immunohistochemistry (IHC), gene expression profiling and molecular profiling
Biopsies can play a big part. Tests can be done on the sample of tissue that was taken to diagnose your cancer (and it can be retested again later if further checks are deemed required). They might use immunohistochemistry (IHC) tests, which look for particular proteins on the surface of the cancer cells. These tests can sometimes tell which type of cell the cancer started in. In the future, techniques called gene expression profiling and molecular profiling should be able to help. Gene expression profiling aims to identify genetic patterns in cancer tissue. It looks at the patterns of genes in the secondary tumour to try to find out where the primary cancer is. Molecular profiling looks at genetic material or particular molecules in the biopsy sample. Its techniques can be used to find out the cancer cell type. These tests are not routinely available.
Heuristic knowledge (epidemiology)
The differences cannot be explained by whether a NEN is situated in the foregut, midgut, or hindgut. For example, Appendiceal, Rectal and Gastric NETs are known to be less prone to metastasis. This may be due to the high rate of incidental ﬁndings during appendectomies and endoscopies.
The majority of the digestive tract is drained by the portal venous system, explaining the dominance of liver metastases in this group of tumours. This also explains the ﬁnding that many nervous system and bone metastases originate from NENs in the lungs. Disseminated tumour cells may directly reach the systemic circulation from the lungs, whereas if originating from the midgut region, they need to ﬁrst pass both the liver and the lungs.
As an example of this heuristic knowledge, one Swedish study indicated that two-thirds of peritoneal metastases will be attributed to Small Intestine NETs (SI NETs). SI NETs and Pancreatic NETs (pNETs) are the most likely to metastasize. The least likely sites to metastasize are the Appendix and Rectum. The same study indicated that in addition to the common metastatic locations of lymph nodes and liver, Lung NETs are more likely to metastasize to the brain and bone than other types. I believe the findings from this study more or less correlates to other information I’ve had access to and also confirms the technical behaviour paragraph above. Authors note: I suspect the study authors were referring to NENs.
In another study from India 75% of unknown primaries were eventually found in the gastroenteropancreatic (GEP) region, i.e. pancreas or in other parts of the gastrointestinal tract, including the stomach, small intestine, colon, rectum, and appendix. In 5 out of 6 patients who presented with mesenteric metastases, primary site was diagnosed as SI NENs. In the same study, more than half of unknown primaries were eventually identified as well differentiated tumours.
What about secondary tumours appearing in common primary locations?
This can be a challenge as epidemiology information for Neuroendocrine metastases in virtually unknown. However, one study from Sweden indicated the following in the document abstract (credit to Wiley Online):
“The epidemiology of metastases in neuroendocrine tumors (NETs) is virtually unknown. The present novel approach took use of two nationwide Swedish registers to assess the distribution of metastatic sites in comparison to adenocarcinoma. 7,334 patients with NET were identified from the Swedish Cancer Registry. Metastatic sites were identified from the National Patient and Cause of Death Registries. Sites of metastasis were investigated depending on the primary site of NET. The metastatic potential of NET was assessed. The liver was the most common site of metastasis (82% of patients with metastases), and the small intestine was the most common source of NET metastases. Of all patients with metastatic lung NETs, 66% had liver metastases, whereas the corresponding number for adenocarcinoma of lung was only 20%. The risk of metastasis was highest if the primary was in the small intestine or pancreatohepatobiliary tract, whereas it was lower with appendiceal and rectal NET. Men had more bone metastases compared to women. The metastatic potential of NETs varies profoundly depending on the primary site. NETs show a clear preference to metastasize to the liver. Surveillance of liver metastases may enable earlier diagnosis and treatment. In liver metastases from NET, the small intestine should be suspected as the primary site, whereas the lung should be suspected in nervous system metastases of NET origin”.
What I also found interesting is that those with metastatic Lung NETs had twice the ratio of ‘extrahepatic’ (outside the liver) than those found in the small intestine and Gastric NET cases. One of the challenges is that some uncommon sites for metastasis are also common sites for primary locations, particularly when involving difficult to treat locations such as the pancreas. In another reference, I did note the most common primary tumours to give rise to pancreatic metastases are lung cancer, breast cancer, renal cell carcinoma, malignant melanoma, carcinoma of gastrointestinal origin and prostate cancer. However, the document is written in ‘anatomical’ terms so whether they include NET variants involved in these primary locations is unclear.
Authors note: Again, I suspect the study authors were referring to NENs.
Multiple Primary Tumours
With NETs there are two scenarios:
1. Multiple primaries in same organ/location (multicentric). This is fairly common in small intestine (SI NETs), stomach/gastric NETs (gNETs), and also found in Lung and pNETs too. NET experts will be aware of the issue and know to look for the possibility. This is an important point with SI NETs as the small intestine is a long and winding organ, although held together by the mesentery. So, a ‘Mark 1 eyeball’ can normally be more efficient in finding NETs in this organ than scans. There is a very well-known surgical technique called “running the bowel” where they check the small intestine for signs of other primary tumours – they can do the same with the large intestine. Additional surgeries due to this lack of knowledge could come with significant morbidity. Multiple ‘nodes’ and ‘lesions’ are common in the thyroid.
2. Multiple primaries in different locations. This is common with Multiple Endocrine Neoplasia (MEN) syndromes (the name gives it away) and these may be metasynchronous. MEN1 for example can have tumours in what is called the ‘3 P’ locations, pituitary, pancreas and parathyroid. Of course, MEN guys may also have multiple primaries in the same organ (multicentric). Read more about MEN by clicking here.
There’s probably a third scenario (for all cancers) and that is multiple primaries with different cancers (i.e a second, third and fourth cancer etc). Synchronous would be really unlucky but metasynchonous is more likely and there are many NEN patients with a second cancer.
What other things or clues can help to find a NEN?
Patient. Very often the patient plays a big part of determining where the primary and other tumours might be by carefully describing symptoms and keeping a diary ready for meeting healthcare professionals.
Incidental Finds. NENs are very often found incidentally during trips to the ER/A&E and also during tests for something else. This is particularly the case with Appendiceal NETs and might explain why the average age of a patient is significantly lower in this type of NEN. Many gastric, small intestine, colon and rectal NETs can be found during endoscopic investigations or other investigations such as screening tests.
Blood tests. We are not yet in a position where these types of tests can diagnose (but we are moving in that direction). In the case of unknown primaries (CUP), sometimes test results can help to locate or confirm where some of these cancers started.
Symptoms and hormone testing
With NETs, symptomatic patients can often test to confirm an elevated hormone marker which may narrow it down to a specific organ or gland. Read more here. Working out whether a patient has a particular syndrome can often be a big clue to the primary location. Read more about the syndromes of Neuroendocrine Cancer by clicking here.
Scans and Endoscopies. Most cancers of a certain size may show up on conventional scanning such as CT, MRI and Ultrasound. Nuclear scans are now playing a bigger part in finding tumours which betray their location through functional behaviour by lighting up or glowing on these specialist imaging systems. Endoscopies (e.g. gastroscopies, colonoscopies, even gastrointestinal pill cameras can be used) can help but just like scans, are not fool proof. Other nuggets include the use of multiphase CT as NETs are known to be hypervascular in nature and liver metastases are better visualised in the late arterial phase – read more about this here. The use of both SSTR PET and FDG PET can often help to localise tumours and this is starting to become popular with the higher Ki67 numbers in grade 2 tumours and grade 3 well differentiated NETs. Generally, with NENs, if you can see it, you can detect it. Read more here.
Hereditary Conditions. Around 5-10% of NENs are hereditary in nature, mostly involving the MEN group of syndromes. Most of those people will know they are at risk of developing NETs from their family history and their doctors should know the most common locations for primary tumours associated with each gene. So, a declared or suspected hereditary syndrome is useful in finding primary tumours if they exist and are proving difficult to find. MEN is not the only hereditary condition related to NETs – read more here.
Biopsies. “Tissue is the issue”. Pathology can very often give really strong clues as to the type of NEN and therefore the likely location of a primary tumour, for example additional tests such as immunostains. Many biopsies will come from secondary cancer (metastases), mostly the liver. Despite all the potential diagnostic routes above, the place the cancer started is sometimes still not found and this may lead to atypical diagnostic/treatment plans and in certain cases this might even include exploratory biopsies via surgery (invasive/minimally invasive), perhaps combined with opportunistic tumour removal if found during the procedure. In cases of unknown primary, the following immunostains testing positive may provide clues: TTF1 (lung), CDX2 (midgut), ISL1 (pancreas) – note this is a really simplified explanation, it’s way way way more complicated than that. This area is advancing quickly – watch this space.
NEC (poorly differentiated Grade 3) vs NET (well differentiated all grades)
Having researched widely, I believe there are 8 key differences between NET and NEC and the most common locations plus other differences can also be a piece of the jigsaw:
- Grade – NEC is by default Grade 3, NETs can be Grade 1, 2 or 3.
- Differentiation – all NETs are well differentiated; NECs are poorly differentiated by default. Very important difference at Grade 3, particularly at Ki67 <55%.
- 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.
- Hormone Secretion – NETs can produce peptide hormones that may be associated with hormonal syndromes. Most NECs usually fail to express hormones or produce hormonal syndromes.
- 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).
- Hereditary Syndromes – NETs are much more likely to be associated with hereditary syndromes such as Multiple Endocrine Neoplasia (MEN).
- 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.
- 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, Pituitary, Thyroid, Parathyroid, Thymus.
Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN)
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 include Oesophagus, Stomach, Biliary Tract and Gallbladder, Duodenum and Ampulla of Vater and Rectum.
I hope this is useful for many NEN patients, particularly those who are looking for a diagnosis or looking for a primary tumour.
Neuroendocrine Cancer – at times, it can really be like looking for a needle in a haystack.
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