Chemistry, toxicology & urinalysis

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• Immunochemiluminometric, 2 site, 2 steps assay that is highly sensitive and specific for monomeric calcitonin

Indications

• A sensitive and specific tumor marker for diagnosis and follow up of C cell disorders, including medullary thyroid carcinoma (MTC) and C cell hyperplasia (CCH)
  • Basal serum calcitonin correlates well with tumor size and extent of metastasis of MTC (Thyroid 2015:25:567)
  • To detect the presence of residual disease, a calcitonin level should be checked 3 to 6 months after the initial operation (total thyroidectomy)
    • Calcitonin doubling time can be used as a prognostic factor (Clin Endocrinol 2010;72:534)
      • If the doubling time is longer than 24 months, the 5 and 10 year survival rates are 100% and 100%, respectively
      • When the doubling time is less than 6 months, the 5 and 10 year survival rates are 23% and 15%, respectively
    • Calcitonin doubling time calculator
• Calcitonin measurement in fine needle aspirate (FNA) washouts of thyroid nodule or suspicious neck lymph node is an additional tool if FNA biopsy findings are inconclusive (Clin Endocrinol 2014;80:135)

Limitations

• Calcitonin negative MTC (nonsecretory MTC) is rare and mostly occurs in sporadic MTC (J Cancer Res Clin Oncol 2016;142:2023)
  • Despite the low or undetectable calcitonin serum level, many of these cases show tissue expression of calcitonin or its precursor by immunostaining or ISH (BMC Endocr Disord 2019;19:45)
• Serum calcitonin can be falsely elevated in several conditions, including chronic renal failure, autoimmune thyroiditis, large cell lung cancers, prostate cancer, mastocytosis, gastrointestinal and pulmonary neuroendocrine tumors, hyperparathyroidism and on proton pump inhibitor drugs treatment (Endocrinol Metab Clin North Am 2017;46:631)
• Heterophile antibodies can cause falsely elevated serum calcitonin levels (Clin Chem 2005;51:208)
• Owing to variability in calcitonin measurements among different commercial assays, individual patient samples should be evaluated using the same assay whenever possible
  • Different assays may use antisera that recognize different epitopes of the calcitonin molecule

Reference ranges

• Gender differences and age related changes in normal calcitonin level exist but no significant ethnic differences observed
• Adults
  • Males: < 19 ng/L
  • Females: < 14 ng/L
• Children: (Clin Chem 2004;50:1828)
  • < 6 months: < 40 ng/L
  • 6 months to 3 years: < 15 ng/L
  • Older children same as adults

Conversion factor

• Multiply by 0.293 to convert from ng/L to pmol/L

Interpretation

• Screening or diagnosis of MTC
  • < 10 ng/L: normal
  • 10 - 100 ng/L: indeterminate (need calcitonin stimulation test)
  • > 100 ng/L: suspected MTC (see Diagram 3)
• Follow up monitoring and prognostic assessment
  • < 10 ng/L: no residual tumor tissue
  • 10 - 150 ng/L: possible local disease (i.e. neck)
  • > 150 ng/l: possible distant metastases (see Diagram 4)
• Reference: Nat Clin Pract Endocrinol Metab 2009;5:35

Indications

• Early diagnosis of neoplastic CCH or micro MTC in RET mutation carriers
• Differentiation MTC from CCH, the preoperative recognition of which should avoid unnecessary thyroidectomies
• Identifying the possible coexistence of nonthyroidal neuroendocrine tumors of the foregut, pancreas, prostate and lung that can be distinguished from a C cell disease by the absence of response to the stimulation test
• Reference: J Clin Endocrinol Metab 2014;99:1656

Methodology

• 2 ways to stimulate calcitonin secretion for diagnostic testing:
  • Calcium stimulation test: give 2.5 mg of elemental calcium/kg bodyweight of 10% calcium gluconate (1 ml = 9 elemental calcium) IV at rate of 5 ml/min for a minimum of 3 minutes
  • Pentagastrin stimulation test: give 0.5 μg/kg body weight of pentagastrin IV for 10 seconds (pentagastrin is now unavailable in many countries)
• Blood is taken at time 0, 2, 5 and 10 or 15 minutes after administration of stimulants to determine calcitonin levels (see Diagram 5)

Interpretation

• Calcium stimulation test and pentagastrin stimulation test show similar diagnostic value in MTC after thyroidectomy (Neuro Endocrinol Lett 2016;37:485)
• Peak stimulated calcitonin (Nat Clin Pract Endocrinol Metab 2009;5:35)
  • < 10 ng/L: absence of C cell disease
  • 10 - 100 ng/L: indeterminate (probable false positive result)
  • 101 - 500 ng/L: probable CCH
  • 501 - 1,000 ng/L: probable MTC
  • > 1,000 ng/L: MTC

Adverse effects

• Nausea, vomiting, abdominal cramping, urgency to micturate, warm feeling, altered gustatory sensation, extremity or facial paresthesia, tachycardia, bradycardia, substernal discomfort and dizziness (Endocrine 2014;46:549)
• Testing is contraindicated in patients older than 60 years old and those with hypertension or coronary artery disease
• Calcium stimulation test is better tolerated than pentagastrin stimulation test

A 30 year old male without a history of underlying disease or medication presented with right thyroid nodule, 3 cm. Fine needle aspiration cytology showed atypical cells suspicious for medullary thyroid carcinoma. His calcitonin level was 30 ng/L (normal < 10 ng/L). What is the most appropriate management of this patient?

1. Check CEA level
2. Consult surgeon for thyroidectomy
3. CT chest / abdomen screening for metastasis
4. Perform calcium stimulation test
5. Repeat fasting calcitonin

D. Perform calcium stimulation test. Calcitonin level is indeterminate (10 - 100 ng/L). After excluding other causes of falsely high calcitonin, calcium or pentagastrin test should be performed in this patient.

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Reference: Calcitonin