Diagnosing the Undiagnosed


Neuroendocrine Cancer is one of a number of “difficult to diagnose” conditions. Many types of Neuroendocrine Cancer come with an associated syndrome and these syndromes can mimic everyday illnesses. In some cases, many people don’t feel ill while the tumours grow. Most types of this cancer are slow-growing but there are also aggressive versions. Although things appear to be improving in diagnostic terms, it can sometimes take years for someone to be finally diagnosed correctly and get treatment, albeit in some cases, too late for any hope of a curative scenario. It’s a very sneaky type of cancer and if left too long it can be life threatening – CLICK HERE to find out why.

The road to a diagnosis of Neuroendocrine Cancer is often not straight or easy to navigate. It’s not only a sneaky type of cancer but it’s also very complex. It’s a heterogeneous group of malignancies with a varied and confusing histology and nomenclature to match. As I said above, many people are asymptomatic for years whilst the tumor grows and some might say that it’s somewhat ‘lucky’ to have symptoms to help aid a diagnosis. Many find that a lack of knowledge of Neuroendocrine Cancer in primary care, doesn’t always produce results. Common misdiagnoses include (but not limited to), Irritable Bowel Syndrome (IBS) and other common digestive diseases, menopause, appendicitis, hypertension, gastritis, asthma. Neuroendocrine Cancer is much more likely to be diagnosed at secondary care if a referral for ‘something’ can be achieved.

……..cue internet searches (Dr Google)

I think the rise and the power of the internet and rise of social media applications is very much helping generate awareness and knowledge of Neuroendocrine Cancer and those looking for a diagnosis may find help in this way. I suspect this instant access to information has played its part in the diagnostic improvements I mentioned above. Take my own efforts for example, I’m a wee Scottish guy with a computer and I’m already accelerating towards a million blog views – there’s clearly a market for what I produce. In terms of those looking for a diagnosis, if only one gets an earlier diagnosis due to my site, I’ll be happy.

Unfortunately, the internet can often be a minefield and in many cases, can lead to quite unnecessary worry for those looking for a solution.

Incoming Questions

I’m contacted almost daily by the ‘undiagnosed’ who suspect they have Neuroendocrine Cancer, often because they appear to be displaying the symptoms of one of the associated syndromes. These are some of my most difficult questions. I’m always very wary of initially agreeing with their assumptions and logic, instead opting for straightforward detective work based on my knowledge of the different types of Neuroendocrine Cancer, knowledge of the best scans, tumour markers, hormone markers. And I always warn them that statistically, they are more likely to have a common condition than the less common Neuroendocrine Cancer.

Many have already had multiple doctor’s appointments and tests. If they have not yet had a scan, I encourage them to try to get one ‘by hook or by crook’. Despite what you read on patient forums and surveys, the vast majority of Neuroendocrine diagnoses will be triggered by a conventional imaging such as CT and/or MRI. If you can see it, you can detect it. 

When I first chat with the ‘undiagnosed’, I find many of them are fairly knowledgeable about Neuroendocrine Cancer and other health conditions, again confirming the power of the internet and the savvy ‘internet patient’. This is fine if you look in the right places of course – for certain things there are more wrong places on the internet than right ones.

If I have time, I’m happy to chat with these people, some are very frustrated – in fact some are so frustrated that they just want a diagnosis of something even if that something is really bad.  Some are not showing anything on any scan but in certain cases, it can be likened to finding a needle in a haystack.

What do you say to someone who is utterly convinced they have Neuroendocrine Cancer but CT/MRI/Octreoscan/Ga68 PET are all clear, Chromogranin A and 5HIAA are in range but they still say they have (say) diarrhea with its potential for literally thousands of differential diagnoses. It’s a tough gig.

Example:

My scan came back normal. That should be good news. But, if there is no tumor, how can I be suffering from all the symptoms of carcinoid syndrome? Is that diagnosis wrong? Are the urine and blood test results wrong? I’m awaiting a MRI scan to take another look to see if the doctor can find anything. I don’t know what they’ll find. I don’t want them to find anything. But I’m afraid of what will happen if they don’t.

Anon

Patient Forums

I always let the undiagnosed know that Neuroendocrine Cancer patients are some of the most friendliest and helpful people you can meet, they will treat you as one of their own. There will be a number of diagnosed people online who have gone through what the undiagnosed are going through, so they will both sympathise and emphasise. But … this can often have the adverse effect of pushing them into believing they must have Neuroendocrine Cancer. This makes for interesting discussions given the number of people who automatically assume that ‘flushing’ or ‘diarrhea’ (as described by the undiagnosed) must be Neuroendocrine Cancer without any reference to the many differential diagnoses and the context of what that actually means in Neuroendocrine Cancer terms.

10 Questions to ask your doctor/specialist for those Diagnosed with Neuroendocrine Cancer (and where to find a specialist)

I once wrote an article for DIAGNOSED NET Patients suggesting 10 Questions to ask their doctor. So I wanted to take a step back in context, using the knowledge I now have, and put myself in the shoes of someone who thinks they may have Neuroendocrine Cancer but is not yet diagnosed.

Key questions to ask your doctor/specialist for those trying to confirm or discount Neuroendocrine Cancer

Dear undiagnosed people. I totally understand your fear. There’s nothing worse than being ill and not knowing what illness you have. I’ve therefore compiled a list of 3 key questions for you to ask – think of it as a tick list of things to ask your doctor to do or check . I have linked several background articles for you to prepare your case. However, I cannot promise your doctor will agree or take any action, in fact some might be annoyed about the lack of trust. However, doing your homework really helps, including diaries and other evidence.

I also wouldn’t say that a negative to all the questions will mean you definitely do not have Neuroendocrine Cancer but at least these questions might provide your doctor and yourself with some food for thought, perhaps leading to the diagnosis of ‘something’. The questions below assume that routine blood tests have been done, including Full Blood Count, Liver, Renal, Bone, Glucose.

Questions for the UNDIAGNOSED to ask their treating physician

“I think I might have a type of cancer known as Neuroendocrine Cancer or Neuroendocrine Tumours (NET) because <<< insert your own story>>>. Would you please consider the following tests and checks:”

1. Chromogranin A (CgA) is a marker which is quite sensitive for Neuroendocrine Tumours, essentially measuring tumour bulk potentially indicating the presence of Neuroendocrine Tumours. There can be other reasons for an elevated CgA figure, including the patient’s use of proton pump inhibitors (PPI) (see the article for an alterative test where this is the case). Read more here – Neuroendocrine Cancer – Tumour and Hormone Marker tests.

2. 5HIAA is a hormone marker for the most common type of NET, particularly if the patient is presenting with flushing and diarrhea. Many NETs have associated syndromes and hormone markers can be a guide to help with diagnostics. Read more about 5HIAA and other hormone markers for different types of NET and different syndromes here Neuroendocrine Cancer – Tumour and Hormone Marker tests.

3. Scans. Most NETs can be seen on a CT scan although liver metastasis can often show more clearly on an MRI. There are also nuclear scan options to confirm conventional imaging findings. Some NETs may be accessible via endoscopy and ultrasounds can also give hints for further investigation. In some cases, nuclear scans will find things that conventional imaging cannot because radionuclides can normally pick up oversecreting tumours. Read more in my article “If you can see it, you can detect it”.

You can hear two NET specialists talking about the issues surrounding the diagnostics here.

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Gallium 68 PET Scans – Into the Unknown

OPINION

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

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’ – read here

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“.  More evidence behind the reason behind this issue can be found here. *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.

20180605_141229

Door to the ‘hot room’

The Results of the Ga68 PET Scan – CLICK HERE

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

 

Endoscopy for NETs – taking the camera to the tumour


endoscopy

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 Echocardiogram and 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 Comedy which 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)

endoscultrasound_2012_1_2_59_117741_f1
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.

Endoscopic retrograde cholangiopancreatography (ERCP)

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)

capsule-endoscopy
“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

sigmoidoscopyA 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

bronchoscopyBronchoscopy 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!

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

patients included

Neuroendocrine Cancer – If you can see it, you can detect it!

octreo-vs-g68
Octreoscan vs Ga68 PET

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)

Liver_Metastases_Ultrasound

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)

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.

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).

Somatostatin receptor-based imaging techniques

owl ga68
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

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.

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.

Read more about Ga68 PET scans by clicking here

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 PET Imaging in Neuroendocrine Tumors” which gives guidance on it’s use – issued by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

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

explorer pet scan

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:

Summary

If you can see it, you can detect it.

Sources:

1. Imaging in neuroendocrine tumors: an update for the clinician, Maxwell, Howe.

2. Appropriate use Criteria for Somatostatin Receptor PET Imaging in Neuroendocrine Tumors.

3.  Useful video from NET Research Foundation about which scans to use for which job.  CLICK HERE to watch.

4.  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.

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

patients included

octreo-vs-g68

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!

CLICK HERE for the scan video

Thanks for reading

Ronny

Hey, I’m also active on Facebook.  Like my page for even more news.

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

Check out my Podcast (click and press play)

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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