COSA:NETs guidelines/Biochemical markers

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Biochemical markers

Neuroendocrine tumours frequently demonstrate elevation of one or more biochemical markers which may be used to follow the course of disease and response to therapy. Some of these markers may be associated with a syndrome due to hormone excess. Positive immunohistochemistry for a marker may not be associated with measurable hormonal overproduction and a syndrome. Hormone production may alter over the course of disease.

Commonly available markers are described. Consideration should be given to referring patients with functioning pancreatic NETs to an endocrinology service.

Serum Chromogranin A (CgA)

Serum Chromogranin A (CgA) is the most established NET marker for diagnosis and monitoring progression or treatment response.

CgA stabilises intracellular vesicles and regulates post-translational protein processing. It is elevated in between 60% and 100% of patients with NETs, including functioning and non-functioning midgut carcinoids, pancreatic islet tumours (functioning and non-functioning) and phaeochromocytomas. Specificity may be lower in midgut NETs. It is proportional to tumour size, and may be useful to estimate prognosis, monitor response to therapy and possibly for monitoring for progression. However the correlation may be lost during SSA therapy.

CgA is more reliable than Ur 5HIAA (urine 5-hydroxyindoleacetic acid) in terms of sensitivity and for detecting small recurrences in follow-up. False positives may result from decreased renal function, atrophic gastritis, liver function impairment, inflammatory bowel disease and proton pump inhibitor (PPI) therapy.

CgA should be used in combination with imaging to measure tumour bulk and response. It can be used for monitoring in the following circumstances:

  • In patients with completely resected disease, for relapse. For example if CgA is trending upwards, (i.e. > 50% baseline outside normal range) and there are no likely causes of a false positive, further investigation should be conducted. Consider a CT scan and functional imaging with octreotide scan.
  • In a patient who has had metastatic disease treated, for the evaluation of response or progression.

CgA is not a measure of tumour bulk for gastrinomas, therefore other hormonal markers need to be measured. It is also not a useful measure for patients on proton pump inhibitors.

Antibody-derived assays are variable and availability is limited to only a few centres. Patient samples should be measured in the same lab consistently. Given the potential inaccuracy of reports of high levels (with anecdotal reports of ±20% in same sample measured on two different occasions, but usual uncertainty of assay ±17%) the laboratory(s) should be asked for confidence intervals and interpatient variation in duplicate samples.

Chromogranin B (CgB)

This assay is not currently available in Australia and NZ (but can be done in the UK), and if available, is preferred to CgA in patients with renal and hepatic impairment.

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Ur 5HIAA

Ur 5HIAA (urine 5-hydroxyindoleacetic acid) is a byproduct of serotonin metabolism and hence serotonin producing tumours such as the classical midgut tumours and, rarely, NETs at other sites. It may be a marker for the risk of carcinoid cardiac disease.

About 95% of patients with carcinoid syndrome have hepatic mets; in the remaining 5% retroperitoneal or ovarian mets bypass the portal circulation, leading to systemic exposure and hence the syndrome.

Ur 5HIAA needs to be collected with strict dietary and medical restrictions. It has sensitivity of 73% and specificity of 100% for midgut carcinoids. CgA is more sensitive (87%).

Substances which may falsely elevate urinary 5-HIAA

Tryptophan-rich foods: avocados, pineapples, bananas, kiwi fruit, plums, eggplants, walnuts, pecans, tomatoes, plantains.

Drugs: paracetamol (acetaminophen), phenobarbital, ephedrine, methamphetamine, nicotine, phentolamine, caffeine, fluorouracil, melphalan, phenacetin.

Substances which may falsely lower urinary 5-HIAA

Drugs: ethanol, imipramine, levodopa, monoamine oxidase inhibitors, phenothiazines, aspiring, isoniazid, streptozotocin, heparin, methyldopa.

Selected subtances which may interfere with measured urinary 5-HIAA (adapted from Maton PN. The Carcinoid Syndrome. JAMA 1988;260(11):1602-5)

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Other serum biochemical markers

  • Pancreatic islet cell tumours: Subject to tumoral functional status, clinical symptoms, histological features and immunohistochemistry:
  • Insulin (blood glucose, C-peptide, Pro-insulin)
  • Gastrin
  • Glucagon
  • VIP
  • Somatostatin
  • Calcitonin
  • Others rarely: ACTHomas, GRFomas, PTH-related protein tumours
  • Pancreatic polypeptide: general tumour marker for pancreatic NETs
Note: Non-functional pancreatic NETs can show increased hormone levels and positive immunohistochemistry without a syndrome: hormonal screen generally not performed in such cases.
  • Pancreatic polypeptide: general tumour marker for pancreatic NETs.
  • Rectal carcinoids: Serum acid phosphatase (in rectal carcinoids if positive on immunohistochemistry), Pancreatic polypeptide and beta-HCG.
  • MEN-1 syndrome suspected: Serum Calcium, PTH and pancreatic polypeptide.
  • Urinary Serotonin and Platelet Serotonin can provide additional information and especially the platelet levels are not influenced by dietary factors. In some studies may be more sensitive that Ur 5HIAA.
  • Serum Histamine for atypical carcinoid syndrome.
  • Others especially in midgut and hindgut carcinoids include neurotensin, substance P and K, enkephalin, alpha-HCG: Not routinely measured.

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Correlation of biochemical marker levels with disease activity and the risk of carcinoid syndrome/carcinoid crisis

Both Chromogranin A and Urinary 5HIAA are proportional to disease bulk and disease progression. However CgA is the more sensitive of the two in all regards and also in detecting small recurrences after radical therapy.

Ur 5HIAA levels are correlated with the risk and presence of carcinoid cardiac disease. There appears to be some correlation between Ur 5HIAA and carcinoid crisis, but literature is scant. Tumour bulk may also be a factor.

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Pre-operative measurement

For an asymptomatic patient, CgA and Ur 5HIAA should be measured prior to surgery. Measurement of other markers should be considered, depending on the tumour site. For example, for pancreatic tumours, request measurement of pancreatic polypeptide.

If the patient is asymptomatic and CgA normal, there is no need to do additional tests (e.g. insulin measurement) as everything else is likely to be normal.

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Frequency of measurement

For patients whose disease has been radically resected:

  • Tumour markers should be measured at 6 months and 12 months and then yearly, lifelong. Where there are poor prognostic factors e.g. high grade tumours, etc, tumour markers should be measured every 6 months, lifelong.

For patients with metastatic disease, where asymptomatic and being observed (low Ki-67 histology):

  • Measure tumour markers every 3 months initially and then less frequently if stable; similarly if on somatostatin analogue therapy.

Ur 5HIAA should always be measured at baseline.

  • If it is elevated, do annual Ur 5HIAA estimations to look at longer term patterns of secretory activity.
  • If Ur 5HIAA is negative at baseline there is no need to measure again.

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References

  1. National Comprehensive Cancer Network. Neuroendocrine tumors (version 2). NCCN Clinical Practice Guidelines in Oncology 2009. [NCCN]
  2. Akerstrom G, Falconi M, Kianmanesh R, Ruszniewski P, Plockinger U, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2009;90(2):203-208. Pubmed ID: 19713712 [Akerstrom]

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