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), there is still a lot of ground to cover. It’s also no secret that certain cancers are difficult to diagnose (NETs is one) and there are a number of reasons why this happens, 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.
I wanted to cover two different aspects of the problem of finding NETs. Firstly, in finding the primary tumour so that the type of NET 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.
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 NETs epidemiology studies can help.
Specialist Knowledge – certain things are known about the behaviour of NETs
Specialists and in particular NET specialists will be aware of the vagaries of NETs 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 NETs will have metastasized to the liver at diagnosis, so whilst it is not impossible to have a primary liver NET, the vast majority of liver tumours found will be secondary (metastases). NET 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 NETs are indeed a heterogeneous group of tumours. The differences cannot be explained by whether the NET is situated in the foregut, midgut, or hindgut. For example, Appendiceal NET is known to be less prone to metastasis. This may be due to the high rate of incidental findings during appendectomies, or because the appendix is an immunological organ where malignant cells can therefore be expected to be frequently recognized by the immune system.
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 our finding that many nervous system and bone metastases originate from NETs 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.
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 it’s quite long although held together by the mesentery, so a ‘Mark 1 eyeball’ can 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 NET patients with a second cancer.
What else helps find a NET?
There are many other clues open to those involved in diagnosing a NET:
Patient. Very often the patient plays a big part of determining where the primary and other tumours might be by carefully describing symptoms.
Incidental Finds. NETs 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 NET.
Blood tests and Hormone Markers. 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 find where some of these cancers started. 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.
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 imaging devices. Endoscopies (e.g. gastroscopies, colonoscopies, even gastro intestinal pill cameras can be used) can help but like scans are not foolproof). Generally with NETs, if you can see it, you can detect it. Read more here.
Hereditary Conditions. Around 5-10% of NETs are hereditary in nature, mostly involving the MEN group of syndromes. Many of those people will know they are at risk of developing NETs 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.
Biopsies. “Tissue is the issue”. Pathology can very often give really strong clues as to the type of NET 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.
Staging. Simple staging can be given if locations of metastases are known. For example in the case of Liver metastases, the stage is automatically Stage 4. However, the full staging definition relies on knowing distant metastases, loco-regional metastases and the full Tumour/Node/Metastases (TNM) definition (size, spread, etc) cannot be fully complete without a primary. Read more here.
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 NETs.
Despite quite advanced scanning and diagnostic testing currently in place, and the extensive knowledge of NET 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 with 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 cancer. It’s also possible (but not common) that any secondary cancer (i.e. metastases) is 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.
Summary
I hope this is useful for many NET 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.
Cancer is a growth industry …literally! More people are being diagnosed than ever before. Fortunately, more people are surviving than ever before. This is against a backdrop of better awareness, better screening in the big population cancers, and to a certain extent better diagnostic tools, all of which is leading to earlier diagnosis.
So how does this affect Neuroendocrine Cancer?
According to the latest SEER database figures for Neuroendocrine Cancer, one reason for the 7 fold increase in incidence rates since the 1970s is all of those things above including better diagnostics. This has led to a revised set of epidemiological information in many countries that have made the effort to accurately update their cancer registries and there are consistent reports of incidence rates way beyond the recognised rare thresholds. Another piece of good news is that the increase in NET incidence is also due to earlier diagnosis. To sum that up – NETs is also a growth industry.
Better diagnostics
Combined with more awareness and education (including the important pathologists), more NETs than ever are being found, and many found earlier. However, it’s not party time yet because there remains far too many misdiagnoses due to the low population of the disease and the difficulty in diagnosing it. I want to focus on scanning (thus the title of the article). Whilst there are really important factors involved in a diagnosis, such as tumor and hormone markers, and biopsies (tissue is the issue), a scan is very frequently what triggers many deeper investigations to unearth a NET, i.e. if you can see it, you can normally detect it (whatever the ‘it’ is). And I include the widespread availability and increasing advances in endoscopy/ultrasounds/cameras which have also been instrumental in picking up many Gastrointestinal NETs.
The Gallium 68 PET Scan
There’s a lot of excitement about the Gallium 68 PET Scan since it was approved by the US FDA. It’s not new though and has been in use in several countries for some time. It’s a ‘nuclear scan’ and can often form part of what is known as a ‘Theranostic Pair’ (i.e. in conjunction with a therapy – read more here).
What does it do?
It comprises two main components – a PET scanning machine, and the use of a diagnostic imaging agent which is injected into the person undergoing the scan. Most machines have an inbuilt CT which forms part of the scan. The agent is a somatostatin analogue labeled radionuclide (Gallium 68) and basically the PET will then be used to see where the peptide/radionuclide mix ‘loiters’ (i.e. where there are concentrations of somatostatin receptors (SSTR) normally indicating ‘focal intense abnormality‘ of the type that is regularly found with NETs.
Imaging Agents. There are different agent variants, namely, DOTATATE, DOTATOC and DOTANOC. In USA, you may sometimes see this referred as NETSPOT which is more of a commercial label for the agent (NETSPOT is a DOTATATE). Ga68 PET or SSTR PET are common descriptors for the entire process regardless of the compound. Clearly the scan works best for those with ‘somatostatin receptor positive’ tumours.
These newer agents have several benefits over the elderly In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2-3 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for radionuclide therapy such as PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET but it will take some time (and money).
Octreoscan vs Ga68 PET
To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine. The slide below is interesting, although it was a small study. However, you can see the treatment changes as a result of a Ga68 PET are quite striking.
This slide from a NET Research Foundation conference confirms the power of more detailed scanning
Appropriate Use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors
I see many people complaining because the cannot get access to a Ga68 PET which is available through their healthcare system or local hospital. Many of these issues are insurance based. Worth pointing out that there are actually recommended usages for the Ga68 PET scan here. For example, it is not recommended for routine surveillance in place of Conventional Imaging (CI).
Any pitfalls with Ga68 PET Scan?
When you look at the study data above, it looks like an excellent addition to the diagnostic and surveillance toolkit for NETs. However, one of the challenges with modern scanning equipment and techniques is the ability to correctly interpret the results – in my opinion, this is almost as important as the efficiency of the machines and radionuclides. This requirement has been acknowledged in many articles and I particularly like this technical paper from a very experienced nuclear medicine physician Professor Michael Hofman from the Centre for Cancer Imaging at the Peter MacCallum Cancer in Melbourne. I had a chat with Professor Hofman who added that this is a very sensitive scan, so often picks up “new” disease, which isn’t really new, just never identifiable on standard imaging. However, there’s an excellent section on pitfalls in interpretation and I’m quoting an abstract below.
“Although GaTate PET/CT is a highly sensitive and specific technique for NETs, the attending physician or radiologist must be aware of various physiologic and other pathologic processes in which cellular expression of SSTR can result in interpretative error. Most of these processes demonstrate low-intensity and/or nonfocal uptake, in contrast with the focal intense abnormality encountered in NETs. Causes of interpretative pitfalls include prominent pancreatic uncinate process activity, inflammation, osteoblastic activity (degenerative bone disease, fracture, vertebral hemangioma), splenunculi or splenosis, and benign meningioma.”
“The highest-intensity physiologic uptake of GaTate is seen in the spleen, followed by the adrenal glands, kidneys, and pituitary gland”
It follows that failure to interpret nuclear scans alongside the patient’s clinical history can sometimes result in two big issues for patients:
1. Unnecessary worry when ‘something’ shows up which is actually a false positive.
2. Something which leads to irreversible treatment when it is was not required.
Just imagine something which is 40 times better than current PET scan technology? That’s what the scientists are working on now. Here’s an example called “EXPLORER“. You can update yourself here. The issue of interpretation will be even more difficult when the new generation of scans appear. There’s an excellent article from Cancer Research UK talking about the modern phenomenon called ‘overdiagnosis’ – readhere
Lanreotide and Octreotide and timing the scan?
From the same technical document referred above, here’s an extract (updated to include Lanreotide). “Uptake at physiologic and pathologic sites may change in patients who undergo concomitant short- or long-acting somatostatin analog therapy, which competes with the radiotracer for bioavailability. We generally discontinue short-acting octreotide for 12–24 hours and perform imaging in the week before the next dose of long-acting Octreotide/*Lanreotide, which is typically administered monthly“. It’s actually the same text as found in the manufacturer’s drug leaflet (click here). More evidence behind the reason for this restriction is found here (please refer to the comments on Ga68 PET – the article also covers the issue of PRRT which is very interesting as a separate subject to the scan timings).
*added by the author for completeness.
Having my first Ga68 PET Scan after 8 years of living with NETs?
When I was offered my very first Ga68 PET/CT at my recent 6 monthly surveillance meeting, I was both excited and apprehensive. I was diagnosed in 2010 and my staging was confirmed via an Octreotide Scan pointing out two further deposits (one of which has since been dealt with). I’ve had two further Octreotide Scans in 2011 and 2013 following 3 surgeries. The third scan in 2013 highlighted my thyroid lesion – still under a watch and wait regime. So far, my 6 monthly CT scans seemed to be adequate surveillance cover and my markers remain normal.
I’m apprehensive because of the ‘unknown’ factor with cancer – what is there lurking in my body that no-one knows about and which might never harm me.
I’m excited because it might just confirm that there is nothing new to worry about.
However, I’m both excited (morbidly) and apprehensive because the scan might find something potentially dangerous. As we know, NETs are mostly slow growing but always sneaky. That said, at least I will know and my medical team will know and be able to assess the risk and decide on a course of action.
Doing the Scan
On 5th June 2018, I attended a very experienced Ga68 PET establishment called Guys Cancer Centre in London. I arrived and was immediately taken under the wing of the nuclear medicine guys who asked me fairly in depth questions about my clinical background. They then inserted a cannula ready for the injection of the radiolabelled tracer. I was then installed in the ‘hot room’ where they injected the radionuclide tracer through the cannula and then I had to remain in the hot room for 1 hour to let the tracer circulate. After 1 hour, I was taken to the PET scanner and it took around 30-35 minutes. Following that I was allowed to leave for home. It was an extremely easy experience and a significant improvement on doing the 3 day Octreotide scan.
An Endoscopy is a procedure where the inside of your body is examined using an instrument called an endoscope. This is a long, thin, flexible tube that has a light source and camera at one end. Images of the inside of your body are relayed to a television screen. Endoscopes can be inserted into the body through a natural opening, such as the mouth and down the throat, or through the bottom. The mouth route is more accurately called a Gastroscopy and the anal route is called a Colonoscopy (or a reduced version called a Sigmoidoscopy). An endoscope can also be inserted through a small cut (incision) made in the skin when keyhole surgery is being carried out.
Gastroscopy
During a routine 6 monthly check-up at the end of 2016, I mentioned to my Oncologist that I was experiencing what appeared to be very minor heartburn and that it was an unusual symptom for me. He called forward my annual Echocardiogramand also ordered up a Gastroscopy.
I received the Gastroscopy paperwork from the hospital for an appointment on 26 Jan 2017. It offered an option for sedation, either a throat spray to numb the area or a sedative where I would probably not know what was going on. My initial thought was the latter even though it meant a longer visit to the hospital with some other constraints. It also meant I would need to check the sedation to assess the risk of NET Crisis. However, having discussed this issue with the department nurse, I was persuaded to go for the throat spray – apparently 80% of people opt for this method. I just couldn’t resist the statistical challenge! There were many advantages to selecting this option including getting rid of the sedation risk, plus I could walk out of the hospital immediately after the 5 minute procedure. The sedation option meant that I would need to remain in the hospital for an extra hour to recover, not drive for 24 hours and be supervised by an adult for 12 hours.
My blood pressure was checked prior to the procedure and systolic was around 145, 10-20 points above my normal ‘cool as a cucumber’ figure. Clearly, despite my deceptively stoic façade, something was making my heart work faster!
I was really put at ease by all 4 people in the room, two nurses, an endoscopic expert and a technician. However, the procedure itself is not what I would call a ‘breeze’. The throat spray was disgusting and said to taste of rotten bananas but personally I thought it was more like rotten fish! For the first 60 seconds (total guess) I found myself wishing I had gone for the sedation but the next minute was better after I had stopped ‘gagging’ and was now breathing fairly normally. I found swallowing easy despite the tube and a nurse was also extracting excess saliva using a similar tool used in a dental procedure. I was also aware that my eyes were watering! The natural reaction of ‘gagging’ came back at least once but only for a second or two. I would be lying if I said it wasn’t scary at the time.
The procedure seemed to be in parts, he checked the oesophagus, pumped air into my stomach for a better view, sprayed some water (not sure why), took a peek in the duodenum which required an extra swallow from me, using another tool, he took a painless routine sample from the stomach lining to test for CLO (Helicobacter Pylori – a bacterium in the lining of the stomach that can cause peptic ulcers), extracted the air, and then the extraction of the endoscope out from the gastrointestinal tract. These endoscopes really are like swiss army knives!
The best bit was the extraction! The other best bit was when he told me there were no real issues. So it was all worth it in the end! If anyone wants a copy of my comprehensive and easy to read 6 page Gastroscopy guide, let me know.
Colonoscopy
The other main type of Endoscopy is the Colonoscopy which enters the gastrointestinal tract in the opposite direction. I’ve had actually both a Gastroscopy and Colonoscopy before in 2008 before I was diagnosed. I offered the mandatory request to do the endoscopy first if using the same scope 🙂 He’d heard it before! On this occasion I was fully sedated. One minute I was talking to the Gastroenterologist, then the next thing I remember was waking up, job done. Less stressful but more time intensive. That said, the preparation for the colonoscopy is no joke. You can read about this in my blog Colonoscopy Comedywhich also includes a light-hearted story about the preparation phase. If you need a laugh, this is really funny.
Although I have not had these, for completeness, I want to mention several associated procedures.
Endoscopic Ultrasound (EUS)
The head of the Pancreas on the left surrounded by the duodenum, stomach to the right
For patients who have, or who are suspected of having pancreatic disease, their doctor may recommend that they undergo a type of procedure called an endoscopic ultrasound, or more often known as EUS. An EUS is a type of endoscopic examination. The EUS is a scan rather than a camera but a camera attachment will be used at some point, perhaps to do additional checks on the way (endoscopic equipment is quite advanced and reminds me of Swiss army knives). It involves the insertion of a thin tube into the mouth and down into the stomach and the first part of the small intestine. At the tip of the tube is a small ultrasound probe that emits sound waves. These sound waves bounce off of the surrounding structures, such as the stomach, small intestine, pancreas, bile ducts, and liver. These sound waves are then recaptured by the probe and converted into black and white images that are then interpreted by your doctor. Because the pancreas sits next to the stomach and small intestine, EUS allows the physician to get very detailed images of the pancreas. This procedure is typically performed in an outpatient setting, and usually takes between 20 and 45 minutes. One of the advantages of performing an EUS is that pancreatic biopsies can be obtained at the time of the examination. These biopsies, often referred to as FNA, or fine-needle aspiration, can allow for your physician to collect tissue samples which can later be analysed under a microscope. Special needles, designed to be used with the EUS scope, allow the physician to insert a small needle through the wall of the stomach or intestine directly into the pancreas. This video explains better: Click here.
ERCP is performed on an outpatient basis under sedation (rarely under general anesthesia). Using a “side-viewing” endoscope, called a duodenoscope, the duodenal “papilla”-(a mound-like structure that houses the opening of the common bile duct and the pancreatic duct)- is identified and manipulated. These areas can be examined and x-ray taken of the pancreatic duct, hepatic duct, common bile duct, duodenal papilla, and gallbladder.The endoscope is passed through the mouth and down into the first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A dye is injected through the catheter into the ducts, and an x-ray is taken. Also called ERCP.
Capsule Endoscopy (camera pill)
“Camera Pill”
Shortly after I was diagnosed, this was mentioned as an option for me as my diagnostic scans were just showing a “mass” and it wasnt 100% clear where my primary tumour was located. It didn’t happen in the end. Capsule Endoscopy involves swallowing a small capsule (the size of the large vitamin pill). The ‘cam-pill’ contains a colour camera, battery, light source and transmitter. The camera takes two pictures every second for eight hours, transmitting images to a data recorder about the size of a portable CD player that patients wear around the waist.
Capsule endoscopy assists in diagnosing gastrointestinal conditions in the small bowel such as: bleeding, malabsorption, chronic abdominal pain, and chronic diarrhoea. Once swallowed the camera moves naturally through the digestive tract. Approximately eight hours after ingesting the camera, patients return to the Endoscopy Unit where the recording device is removed by the nurse, the images are downloaded to a computer and evaluated. The Capsule is disposable and will be passed naturally in the bowel movement.
Sigmoidoscopy
A flexible sigmoidoscopy is a procedure that is used to look inside the rectum (back passage) and lower part of your large bowel (descending colon) and so is like an abbreviated version of a colonoscopy.
Bronchoscopy
Bronchoscopy is a procedure that allows the doctor to examine your trachea (windpipe), bronchi (branches of the airway) and some areas of the lung. A short thin flexible tube with a mini camera built into its tip, called a ‘bronchoscope’, is used for this procedure. The bronchoscope is usually passed through your mouth or nose, into your trachea and bronchi. The doctor can then get a clear view of your airways. During the procedure, the doctor may take samples of tissue (biopsy) or respiratory secretions for examination. Bronchoscopies can also be used for ablation purposes. You may be interested in this award-winning biopsy and ablation service offered by the Royal Free Hospital in London UK – Innovation at Royal Free – Lung Biopsy and Radio Frequency Ablation Service
Thanks for reading about how physicians can take the camera directly to the sites of suspected tumours!
Scanning is a key diagnostic support and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans do not normally confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will be able to find some evidence of tumour activity in 90-95% of cases. However, some are cunningly small or hiding and it can be like trying to find a needle in a haystack.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). The differences between scan types are more quality (sensitivity) related as new technologies are introduced.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon“. I replied “whatever you want me to do“. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body, he wanted to scan me. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the roller coaster. Medicine is not an exact science (not yet anyway) but here’s something I believe is a very common occurrence in all cancers – If your doctors don’t suspect something, they won’t detect anything.
There’s frequent discussion about the best types of scans for different types of NETs and which is best for different parts of the anatomy. There’s also different views on the subject (including in the medical community), However, a few well known facts can be gleaned from authoritative NET sources:
Conventional Imaging
Computed Topography (CT)
CT scans are often the initial imaging study for a patient presenting with signs or symptoms suggestive of many cancers including NET. These studies are most useful for disease staging and surgical planning as they provide excellent anatomic detail of the tumors themselves and surrounding structures. Primary NETs (GI and lung NETs) and their metastases are generally hyperenhancing with IV contrast and are best seen in the arterial phase of a triple phase CT scan.
In primary NETs, the average sensitivity of a CT scan is 73%. CT scans have even better sensitivity in detecting NET metastases, as they demonstrate 80% sensitivity for liver metastases (but see MRI below) and 75% sensitivity for other metastases (non-liver). This modality is also useful when the primary tumor site is unknown. In one single-institution retrospective study, it was the most common study ordered to look for an unknown primary tumor site and was able to uncover the primary in 95% of cases.
Magnetic resonance imaging (MRI)
MRI is the best conventional study to detail liver metastases in NETs. It is not as useful as CT for the detection of primary small bowel lesions or their associated lymphadenopathy, but is good for the detection of primary pancreatic NETs. A study comparing MRI, CT and standard somatostatin receptor-based imaging (OctreoScan) reported 95.2% sensitivity for MRI, 78.5% sensitivity for CT and 49.3% sensitivity for the OctreoScan in detecting hepatic metastases. MRI also detected significantly more liver lesions than the other two modalities.
You may see something called Magnetic Resonance Cholangiopancreatography (MRCP). Magnetic resonance cholangiopancreatography (MRCP) is a special type of magnetic resonance imaging (MRI) exam that produces detailed images of the hepatobiliary and pancreatic systems, including the liver, gallbladder, bile ducts, pancreas and pancreatic duct.
Ultrasound (US)
The primary role of conventional ultrasound in neuroendocrine disease is detection of liver metastases and estimation of total liver tumor burden. This technique has the advantages of near-universal availability, intraoperative utility, minimal expense and lack of radiation. Most examinations are performed without contrast, which limits their sensitivity (compared with CT and MRI). I know in my own situation, US was used as a quick check following identification of multiple liver metastasis during a CT scan. I’ve also had US used to monitor distant lymph nodes in the neck area but always in conjunction with the most recent CT scan output.
Endoscopic Ultrasound (EUS)
With increased access to endoscopy, NETs in the stomach, duodenum, and rectum are increasingly incidentally detected on upper endoscopy and colonoscopy. Patients are frequently asymptomatic without any symptoms referable to the a NET (i.e. non-functional). EUS has also been used to survey patients at increased risk of developing pancreatic NETs. For example, patients with multiple endocrine neoplasia (MEN). They are also frequently used in conjunction with biopsies using fine needle aspiration (FNA) guided by EUS.
Somatostatin receptor-based imaging techniques
Graphic courtesy of Advanced Accelerator Applications
Somatostatin is an endogenous peptide that is secreted by neuroendocrine cells, activated immune cells and inflammatory cells. It affects its antiproliferative and antisecretory functions by binding to one of five types of somatostatin receptors (SSTR1- SSTR5). These are G-protein coupled receptors and are normally distributed in the brain, pituitary, pancreas, thyroid, spleen, kidney, gastrointestinal tract, vasculature, peripheral nervous system and on immune cells. Expression of SSTRs is highest on well-differentiated NETs. Somatostatin receptor type 2 is the most highly expressed subtype, followed by SSTRs 1 and 5, SSTR3 and SSTR4.
It must be noted that even the most modern scans are not an exact science. Radionuclide scans are like conventional imaging, they can be subject to physiological uptake or false positives, i.e. they can indicate suspicious looking ‘glows’ which mimic tumours. This article explains it better than I can – click here.
The ubiquity of SSTRs on NET cell surfaces makes them ideal targets for treatment (e.g. Somatostatin Analogues (Octreotide/Lanreotide) and PRRT), but also for imaging. There are two primary types of somatostatin receptor-based imaging available:
Octreoscan – In111 based
The most common (currently) is the OctreoScan or Somatostatin Receptor Scintigraphy (SRS), which uses the ligand 111In-DPTA-D-Phe-1-octreotide and binds primarily to SSTR2 and SSTR5. In its original form, it provided a planar, full body image. In modern practice, this image is fused with single photon emission computed tomography (SPECT) and CT. This takes advantage of the specificity of the OctreoScan and the anatomic detail provided by SPECT/CT, improving OctreoScan’s diagnostic accuracy. These improvements have been shown to alter the management in approximately 15% of cases, compared with just OctreoScan images. In primary tumors, the OctreoScan’s sensitivity ranges from 35 to 80%, with its performance for unknown primary tumors dipping beneath the lower end of that range (24%). Its ability to detect the primary is limited by the size but not SSTR2 expression, as tumors less than 2 cm are significantly more likely not to localize but do not have significantly different SSTR2 expression than their larger counterparts.
Octreoscan – Tc99m based
In one study, it was shown that sensitivity and negative predictive
values of Tc-99m-Octreotide scan is significantly higher than that of CT
and MRI. Using Tc-99m instead of In-111 had several advantages that
include better availability, cheaper and higher quality images. In
addition, to less radiation exposure to both patients and nuclear
medicine personnel. In the absence of Ga68 PET, this could prove a reliable alternative. Please note this scan is completed in a single day vs In111 Octreotide time of 2-3 days.
Ga68 PET (or SSTR PET in general)
The newest somatostatin receptor-based imaging modality, although it has been around for some time, particularly in Europe. The most common of these labeled analogs are 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE. They may be known collectively as ‘SSTR-PET’. Additionally, the DOTATATE version may often be referred to as NETSPOT in USA but technically that is just the commercial name for the radionuclide mix.
These peptides are easier and cheaper to synthesize than standard octreotide-analog based ligands, boast single time point image acquisition compared to 2 or 3 days with Octreoscan. Its superior spatial resolution derives from the fact that it measures the radiation from two photons coincidentally. SPECT, in comparison, measures the gamma radiation emitted from one photon directly. This results in different limitations of detection – millimeters for 68Ga-PET compared with 1 cm or more for SPECT. There are a few choices of ligands with this type of imaging, but the differences lie primarily in their SSTR affinities – all of the ligands bind with great affinity to SSTR2 and SSTR5. 68Ga-DOTANOC also binds to SSTR3. Despite these differences, no single 68Ga ligand has stood out as the clear choice for use in NETs. As with standard somatostatin receptor-based imaging, these 68Ga-PET studies are fused with CT to improve anatomic localization.
Comparison studies between 68Ga-PET and standard imaging techniques (CT, OctreoScan) have universally demonstrated the superiority of 68Ga-PET in detection of NET primary tumors and metastases. Two early studies compared 68Ga-DOTATOC to standard somatostatin imaging (SRS)-SPECT and CT. Buchmann et al. reported that 68Ga-DOTATOC detected more than 279 NET lesions in 27 patients with histologically proven NETs, whereas SRS-SPECT detected only 157. The greatest number of lesions were detected in the liver. 68Ga-DOTATOC found more than 152 hepatic lesions, while SRS-SPECT found only 105, resulting in a 66% concordance rate between the two modalities. The concordance for abdominal lymph nodes was worse at 40.1%. Cleary these advantages are going to impact on treatment plans, some needing to be altered. In addition, 68Ga-DOTA PET imaging can be used to determine which patients might benefit from use of Somatostatin Analogues (Octreotide/Lanreotide) and PRRT – you can read more about this integrated and potentially personalised treatment in my article on ‘Theranostics‘ – click here.
It’s worth pointing out that SSTR PET is replacing previous types of radionuclide scans, mainly Octreoscan (Indium 111) and is not replacing conventional imaging (CI) such as CT and MRI etc. Whilst SSTR-PET has demonstrated better sensitivity and specificity than CI and In-111, there are specific instances in which SSTR-PET is clearly preferred: at initial diagnosis, when selecting patients for PRRT, and for localization of unknown primaries. For patients in which the tumor is readily seen on CI, SSTR-PET is not needed for routine monitoring. The Journal of Nuclear Medicine has just published “Appropriate Use Criteria for Somatostatin Receptor PETImaging in Neuroendocrine Tumors” which gives guidance on it’s use – issued by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).
Other PET Scans
18FDG PET
18-Fluoro-Deoxy-Glucose PET (FDG PET) is used to detect malignancy for a variety of tumor types. Unfortunately, its utility has not been borne out in NETs, as the majority of NETs tend to be relatively metabolically inactive and fail to take up the tracer well. However, high-grade NETs are more likely to demonstrate avid uptake of 18FDG, giving these scans utility in identifying tumors likely to display more aggressive behavior.
18F-FDOPA PET
The use of Fluoro-18-L-Dihydroxyphenylalanine (18F-FDOPA) in PET was developed in the 80’s for the visualisation of the dopaminergic system in patients with degenerative disorders, such as Parkinson’s Disease and related disorders. The first publication on the use of 18F-FDOPA PET for brain imaging was in 1983, which was followed by many others on the use of 18F-FDOPA PET for the diagnosis of Parkinson’s disease. Years later, in 1999 the first publication on the use of 18F-FDOPA PET for imaging of neuroendocrine tumour appeared. The value of 18F-FDOPA PET has now been proven for the diagnosis and staging of many neuroendocrine tumours, brain tumours and congenital hyperinsulinaemia of infants.
18F-FDOPA is accurate for studying well differentiated tumours. However the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of somatostatin receptors (SSTR) such as Medullary Thyroid Carcinoma, Neuroblastoma, Pheochromocytoma), and others that cannot be accurately studied with Somatostatin SSTR scans such as the OctreoScan (Somatostatin Receptor Scintigraphy (SRS)), which uses the ligand 111In-DPTA-D-Phe-1-octreotide or the newer 68Ga DOTA-peptides.
I-MIBG
Radioiodinated (123I) metaiodobenzylguanidine (MIBG) is an analog of norepinephrine that is used to image catecholamine-secreting NETs such as pheochromocytomas, paragangliomas and glomus tumors. It can also be used to look for Neuroblastoma in children. In patients with functional pheochromocytomas or paragangliomas, this modality has a sensitivity of 90% and positive predictive value of 100%. However, it has limited use in Gastrointestinal (GI) NETs, as this modality was positive in only 49.1% of patients. In the same cohort of patients, OctreoScan was positive in 91.2%. As an imaging tool, this study is best used to confirm a diagnosis of pheochromocytoma or paraganglioma and define the extent of metastatic disease in these tumors. (Note – the Ga68 PET is rising in prominence though). Its most practical use in GI NETs may be to determine whether patients with metastases may benefit from treatment with 131I-MIBG (a form of radiotherapy).
Miscellaneous Scans
Parathyroid Scan – Sestamibi
Sestamibi scanning is the preferred way in which to localize diseased parathyroid glands prior to an operation. This parathyroid scan was invented in the early 1990’s and now is widely available. Sestamibi is a small protein which is labeled with the radio-pharmaceutical technetium99 (Tc99m). This very mild and safe radioactive agent is injected into the veins of a patient with hyperparathyroidism (parathyroid disease) and is absorbed by the overactive parathyroid gland. Since normal parathyroid glands are inactive when there is high calcium in the bloodstream, they do not take up the radioactive particles. When a gamma camera is placed over the patient’s neck an accurate picture will show the overactive gland. Only the overactive parathyroid gland shows up…a very accurate test.
The Sestamibi scan will display the hyperactive gland which is causing hyperparathyroidism in about 90 percent (90% sensitivity) of all patients. If the Sestamibi does show the hyperactive gland it is almost always correct (98-100% specificity). It takes approximately two hours to perform the Sestamibi scan after it has been injected. Pictures of the neck and chest are usually taken immediately after the injection and again in 1.75 to 2.0 hours (shown above). Newer techniques allow for more complete two and three dimensional images to be obtained of a patient’s neck. This technique is called SPECT scanning (Single Proton Emission Computerized Tomography) but it is usually not necessary.
Skeletal Scintigraphy (bone scan)
Quite often, bone metastases in NETs will be found via conventional imaging or special to NET nuclear scans such as Ga68 PET or MIBG. However, a bone scan can often find them or confirm findings of scans looking for NETs.
Skeletal scintigraphy is a special type of nuclear medicine procedure that uses small amounts of radioactive material to diagnose and assess the severity of a variety of bone diseases and conditions, including fractures, infection, and cancer.
Nuclear medicine imaging procedures are non-invasive and — with the exception of intravenous injections — usually painless medical tests that help physicians diagnose and evaluate medical conditions. These imaging scans use radioactive materials called radiopharmaceuticals or radiotracers. Radioactive energy emitted from the radiotracer is detected by a special camera or imaging device that produces pictures of the bones called scintigrams. Abnormalities are indicated by areas of abnormal bone that take up more or less of the radiopharmaceutical which appear brighter or darker than normal bone on the scintigram.
Because nuclear medicine procedures are able to image the functions of the body at the molecular level, they offer the potential to identify disease in its earliest stages as well as a patient’s response to therapeutic interventions. In fact, a bone scan can often find bone abnormalities much earlier than a regular x-ray exam.
Taking the camera inside and directly to the Tumour
Of course there are other ways to “see it” via several types of Endoscopy procedures – taking the camera to the tumour. Read my article about this by clicking here
A look to the future of PET Scans
Just imagine something which is 40 times better than current PET scan technology? That’s what the scientists are working on now. Here’s an example called “EXPLORER“. Clearly there are more answers required in order to see if this is suitable for use with NETs (i.e. will it work with our radionuclide tracers etc) but it is very exciting and like something out of Star Trek. A little bit of me is worried about ‘overdiagnosis’ so interpretation of something that detailed will be very important to avoid unnecessary worry. Read more here and there is a later update here. Check out this cool video of the 3D images:
4. Useful video from NET Research Foundation about which scans to use for which job. CLICK HERE to watch.
5. Useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect. Worth a look. CLICK HERE for the scan video
Sooner we can ALL get access to the latest radionuclide scans the better – this is currently an unmet need in many countries.
If you are any doubt about which type of scan is best for you and their availability, please consult your specialist.
Please Share this post for Neuroendocrine Cancer awareness and to help another patient
Scanning is a key diagnostic and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans can’t (yet) confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will normally find some evidence of most tumour activity.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). However, technology is improving all the time and you can read about this in my blog Neuroendocrine Cancer – Exciting times Ahead.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon”. I replied “whatever you want me to do”. He wanted to scan me. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the rollercoaster. Here’s something I always say I believe is so much better than the impractical early diagnosis messages that seem to pervade our community: If your doctors don’t suspect something, they won’t detect anything and I believe this is a very frequent outcome of many diagnoses for many cancers (not just NETs).
There’s frequent discussion about the best types of scans for different types of NETs and even for different parts of the anatomy. This is correct and there’s also different views on the subject (including in the medical community), However, a few well known facts that can be gleaned from authortative NET sources. I found this useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect. Worth a look.
Sooner we can all get access to the latest radionuclide scans the better!
