A spotlight on Chromogranin A

What is Chromogranin A?

Chromogranin A (CgA) is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it’s a good marker to use with Neuroendocrine Neoplasms. It is said to be a measure of tumour bulk. Depending on the test kit being used, you may also see test results for Chromogranin B (CgB) alongside CgA. CgB is said to be less affected by false positives and forms a useful adjunct to the more established chromogranin A measurement. The brand of test kit which includes CgB tends to be confined to Europe.

Immunohistochemical Testing. CgA is one the most commonly used immunohistochemical (IHC) markers for neuroendocrine cells and their tumours. You may find the mention of CgA in your biopsy reports from tissue samples. You should not necessarily expect an elevated CgA blood test because your IHC biopsy report states the tumour is positive for CgA.

Functional/Non-functional

NETs can be ‘functional’ meaning they oversecrete certain hormones leading to a hormonal syndrome associated with their primary tumour. These are known as functional tumours. Most NETs are actually non-functional, it’s not advisable to assume a direct correlation between elevated and normal readings of CgA and a functional or non-functional tumour.

The controversial bit

Despite CgA being the only widely available tumour marker for most Neuroendocrine Neoplasms, some doctors, particularly in US, have lost faith in its utility and no longer recommend its use in some scenarios. Reference 4, NCCN Guidelines (Principles of Biochemical Testing) state ” In select cases, chromogranin A may have prognostic value, but treatment decisions are not based solely on changes in chromogranin” and “…… in general should not be relied upon in isolation as a diagnostic test“. However, it remains the gold standard in many countries, despite being tarnished by this controversy.

Proton Pump Inhibitors (PPIs)

One of the biggest disadvantages of CgA is that the results can be skewed by those taking Proton Pump Inhibitors (PPIs), a drug prescribed for acid reflux conditions such as gastroesophageal reflux disease (GERD), making it widely used in the general population in many countries. Many NET patients will have been prescribed these drugs prior to diagnosis and will be already taking PPIs at diagnosis. For some of these patients there will be a connection with their condition, but most will not. In the long-term, this has the result of increasing gastrin levels which can lead to an increase of CgA in the blood even for some time after discontinuing. Opinions differ but many texts I found did suggest stopping PPIs for 1 or 2 weeks before the CgA blood test. Some sites also added 24 hours for ceasing Histamine Type-2 Receptor Antagonists (H2 Blockers), which do a similar job.

In addition to the issue with PPIs, CgA levels may also be elevated in other common illnesses, including but not limited to, severe hypertension and renal insufficiency – see chart below.

Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M. Chromogranin A–biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol. 2010 Sep;17(9) 2427-2443. doi:10.1245/s10434-010-1006-3. PMID: 20217257.

Note: There is evidence of online comments on the reference quoted above suggesting a group of scientists disagree with the data used.

Reference 3 below is more accessible than the one above which sits behind a paywall.

Abstract from CASPAR Study published October 25 2024

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. Patients and Methods:

A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value > 100 ng/mL in the following CgA concentration was considered positive.

Results:

153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%—95·5%, p < 0·001), sensitivity 34·4% (25·6%—44·3%), positive predictive value 57·9% (45·0—69·8), negative predictive value (NPV) 84·3% (80·5—87·6), and area under the curve 0·73 (0·67—0·79).

Conclusions:

Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.

Things to know about test results and restrictions

It’s really important to understand these points when discussing test results and restrictions:

1. Test Name. Different test kits may name the test differently, normally only slight changes. Fortunately, there seems to be a common theme – simply “Chromogranin A” although some may abbreviate it to CgA or CHGA.

2. Results. A positive result may indicate the presence of a tumour but will not tell the doctor what type it is or where it is. Additionally, to amplify above, the quantity of CgA is not associated with the severity of a patient’s symptoms associated with one of the NET hormonal syndromes but is associated with the tumour burden – the mass of tumour. Test results cannot be interpreted as absolute evidence for the presence or absence of malignant disease. Imaging and tissue sampling are usually a stronger indication.

Results can differ between laboratories in terms of the unit of measure and the reference range. This can cause havoc and misunderstandings in patient groups as people try to compare apples with pears. Always know and state your lab data before asking the question in patient groups. This is important so you can filter out the usual irrelevant responses you may receive.

When interpreting the result of the CgA blood test, caution is recommended, bearing in mind the multitude of factors that may lead to both false positive and negative results (as per controversy above).

If concentrations of CgA are elevated prior to treatment and then fall, then treatment is likely to have been effective. If following treatment of the tumour concentrations begin to rise again, then the patient may have a recurrence of the tumour. As above, imaging remains a potentially stronger indication.

Elevated CgA is a constant and somewhat excitable discussion point in patient forums and not just because of the confusion caused by not adding the unit of measurement when asking questions in a patient forum. Some people get quite excited about a single test result. I refer to Dr Woltering et al where it clearly states that changes in CgA levels of more than 25% over baseline are considered significant and a trend in serial CgA levels over time has been proven to be a useful predictor of tumour growth (i.e. a single test result with an insignificant rise may not be important on its own). Dr Woltering also gives good advice on marker tests when he says, “normal is normal” (i.e. an increased or decreased test result which is still in range is normal and not an indication of more or less growth).

3. Restrictions. Different test kits not only produce different testing score outputs (unit of measure and reference ranges) but there is the possibility of different testing constraints/restrictions. Other than the requirement to temporary halt PPIs, there are no major restrictions (but always obey your lab test instructions which should be provided before the test). However, according to several sources (including Reference 3 below), patients should undergo an overnight fast (anything between 8-12 hours is mentioned). Reference 3 also mentions exercise, but an overnight fast would seem to suffice for both in most individual cases. As above, always obey your lab test instructions which should be provided before the test.

Note: Healthcare organisations buy their test kits from commercial companies, there are several different test kits in use, each with potentially different instructions. Labs may also have different processes for handling and storing. Using the same lab is preferable but not always possible.

My own experience as a Small Intestine NET

My Chromogranin A was elevated at diagnosis (371 pmol/L (reference range <60). It remained elevated after removal of the primary and locoregional tumours, and after 7 months of somatostatin analogues (377 pmol). It only returned to normal range after liver surgery. It spiked twice by a small amount 3 months after liver surgery and then dropped back into normal range after a small surgery (lymphadenectomy) in Feb 2012. It has been in normal range since.

I’m non-functional and stable so I’m currently tested every 12 months (previously 6 months and 3-4 monthly in the early years). Ad hoc tests could be conducted in the event of any issues. I’m always told to fast overnight for CgA but as I’m normally undergoing other tests, some of which are fasting, it’s not an added issue for me. The sample in its tube is always placed in ice immediately after the tube is sealed and labelled; then sent straight to the laboratory.

Opinion: Test Instructions and Restrictions

Given the wide discrepancies that exist on the fasting and contraindications that can be found on the internet, plus differences between labs, I’ve always been sceptical of the instruction sheets handed out from various hospitals. I think there are a number of issues:

1. Hospital instructions may often be compiled by people who are not comparing with the test assay in use but instead finding out of date info on the internet and copy and pasting.

2. Others may just be ‘versioning’ issues as instructions are not updated following the commissioning in the laboratory of a new or updated test assay exacerbated by the fact that many tests are sent to off-site labs, but the offsite lab has not provided test instructions i.e. the hospital ordering the test is responsible for updating and issuing the instructions to patients but is unaware of changes in assay instructions from the lab.

3. Judging by the amount of people asking for advice in my patient group, some testing sites are not providing test instructions. This can only provide skewed results and/or confusing outputs not fully understood.

Always follow your own lab instructions, regardless of this blog post

Disclaimer

I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.

Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.

Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.