Neuroendocrine Cancer – If you can see it, you can normally 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.

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 – 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.

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).

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.  Read more about the use of 18F-FDOPA in ‘endocrine tumours’ here.  Please bear in mind that more recent Ga68 PET studies may supersede some of the data mentioned. If in doubt ask your specialist.

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). Please bear in mind that more recent Ga68 PET studies may supersede some of the data mentioned. If in doubt ask your specialist. 

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 Sestsestamibiamibi 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

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. Radiology for Patients,

4. Role of 18F‐FDOPA PET/CT imaging in endocrinology.  (added for information on 18F F-DOPA)

5. Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]tracers, [11C]/[18F]-HTP). (added for information on 18F F-DOPA)

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

7.  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.

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

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Author: Ronny Allan

Facebook: https://m.facebook.com/NETCancerBlog and https://m.facebook.com/RonnyAllanBlog twitter: @ronnyallan1 twitter: @netcancerblog

3 thoughts on “Neuroendocrine Cancer – If you can see it, you can normally detect it!”

  1. Love it, Ronny!

    Thanks for the great article, and all the references too. Keep up the good work.

  2. My concern with CT scans is the huge amount of radiation for each one. From what I read each CT scan is worth about 10 chest x-rays. I would rather do MRI’s. Opinions?

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