Serum tumor markers improve thyroid cancer management
Thyroid cancer is a common malignant tumor of the head and neck and endocrine malignancy with insidious onset, often with painless thyroid nodules as the initial clinical manifestation. Common thyroid cancer can be classified into differentiated thyroid cancer (DTC), undifferentiated thyroid cancer, medullary thyroid cancer (MTC) and so on. In recent years, thyroid cancer has become one of the most common malignant tumors with rapidly increasing incidence in China, and according to the 2013 Annual Report of China Tumor Registry, thyroid cancer has occupied the eighth place among the top 10 malignant tumors in women.
With the development of biotechnology, many tumor markers related to the occurrence, development and regression of thyroid cancer have been discovered, such as thyroglobulin (Tg), calcitonin, galactose lectin-3, cytokeratin-19, vascular endothelial growth factor, human bone marrow endothelial cell markers, etc. On April 25, “Serum Tumor Markers The multidisciplinary forum on “How to improve the management of thyroid cancer” was held in Wuhan, China on April 25.
Prof. Luca Giovanella, Director of the Center for Nuclear Medicine and PET-CT from the Southern Swiss Institute of Oncology, gave a new presentation on the application of highly sensitive Tg and Calcitonin in the diagnosis and treatment of thyroid cancer, and also introduced the European application of Calcitonin in the screening of patients with thyroid nodules. Experts from the fields of clinical surgery, endocrinology, nuclear medicine and laboratory exchanged the latest advances in thyroid cancer diagnosis and treatment, and discussed in depth the important clinical value of thyroid cancer serum markers, especially Tg and Calcitonin, in the application of thyroid cancer diagnosis and treatment.
Thyroglobulin: Guiding postoperative evaluation and monitoring of differentiated thyroid cancer
More than 90% of thyroid cancer is differentiated thyroid cancer (DTC), and clinical treatment usually includes surgical resection, postoperative 131I (iodine 131) therapy and TSH (thyroid stimulating hormone) suppression therapy. Approximately 30% of patients with DTC develop recurrence or metastasis, with 2/3 of them occurring within 10 years after surgery, and in a few cases, recurrence or metastasis occurs many years after surgery. Therefore, lifelong follow-up is required for patients with thyroid cancer.
For patients with DTC who have had total thyroid clearance (after total surgery and 131I nail clearance), there should no longer be a source of Tg in the body; if Tg is detected in the serum, it often indicates residual or recurrent DTC lesions. Therefore, Tg is a first-line indicator and an important component of postoperative evaluation and monitoring of DTC patients.
According to the 2012 National Comprehensive Cancer Network guidelines for the diagnosis and management of DTC, follow-up at 6 and 12 months after DTC surgery is recommended, with mandatory investigations including physical examination and measurement of Tg and its antibody (TgAb). If there is no positive finding, the follow-up should be done annually thereafter; if there is an abnormal finding, or if the initial assessment of the tumor stage is T3/4 or M1, 131I whole-body imaging after TSH stimulation should also be considered. Depending on the review (especially the Tg level), reoperation, continuous TSH suppression or 131I therapy may be chosen.
So, how can the presence of Tg be assessed? Tg in the basal state can be measured, i.e. the concentration of Tg is measured while taking thyroid hormone. TSH-stimulated Tg can also be measured by either discontinuing thyroid hormone or by applying recombinant TSH, both of which measure Tg by raising the TSH level in the patient’s body. post-TSH-stimulated Tg measurements are usually higher than basal state Tg values during thyroid hormone administration.
According to Dr. Luca Giovanella of the Southern Swiss Institute of Oncology, the Tg assay must be highly sensitive, have reliable results, and must be calibrated by an international reference, in addition to which the manufacturer should provide information on its Tg assay reagents, telling the laboratory what their limit of detection (LoD) is, what their limit of quantification (LoQ) is, what their functional sensitivity (FS) is, and how their LoQ and FS are defined.
These values are different for different Tg assays. The appropriate Tg reference range should be established based on a specific population, and clinicians should also carefully evaluate the means of Tg detection so as to better facilitate the clinical follow-up of thyroid cancer patients.
When thyroglobulin antibodies (TgAb) are present in patients, TgAb can bind to Tg and affect the binding of signal molecule labeled antibodies or capture antibodies to Tg, leading to the occurrence of low or false negative Tg test results. Therefore, the interference of TgAb needs to be excluded during the Tg determination. If the traditional immunoradiometric method (IMA) is used, some of the negative results of the Tg assay are actually due to interference by TgAb.
Therefore, Tg must be detected by a highly sensitive Tg immunoassay. Also, for TgAb, each clinical laboratory should establish two reference values: one based on the population without thyroid disease for the diagnosis of autoimmune thyroid disease; the other is the limit of quantification (LoQ) of the assay, which is used as the upper limit of normal for monitoring postoperative recurrence in patients with DTC.
Changes in Tg assay methods can result in different Tg results measured before and after in the same patient, thus affecting the accuracy of dynamic monitoring assessment. Serum Tg should be measured by a validated immunoassay that is calibrated against an international reference (CRM 457). When the assay changes, the patient must be re-evaluated, i.e., re-evaluated under the new assay, in order to facilitate a correct patient dynamic monitoring result.
Similarly, changes in the TgAb assay method can affect the dynamic assessment of monitoring. It is recommended to use a quantitative immunoassay standardized by the international reference MRC 65/93 for the detection of serum TgAb.
In addition, preoperative determination of Tg and TgAb in patients with suspected or confirmed DTC is not recommended for preoperative benign or malignant diagnostic purposes, but should be used as an “in vivo” recovery test to assess the reliability of Tg as a postoperative tumor marker. If preoperative patients are negative for Tg and TgAb, then these two markers are not appropriate for postoperative follow-up of DTC patients.
The results of a meta-analysis of follow-up Tg in patients with DTC showed that serum Tg in the basal state measured using a highly sensitive Tg assay with a functional sensitivity <0.1 ng/mL had an extremely high negative predictive value in the monitoring of patients with DTC. this was also demonstrated by the results of a study by Cláudia C.D. Nakabashi et al.
Therefore, post TSH stimulation Tg assay can be avoided in patients with basal high sensitivity serum Tg assay values lower than the functional sensitivity of the assay (<0.1ng/mL) in the presence of negative TgAb, and post TSH stimulation Tg assay needs to be considered when basal Tg levels are higher than the functional sensitivity values.
The Elecsys® TgII was approved by the CFDA in China on December 9, 2013 and has a further improved sensitivity compared to Tg, with a functional sensitivity of 0.09 ng/mL. As described above, the basal Tg test can partially replace the TSH-stimulated Tg test using a test with a functional sensitivity of 0.1 ng/mL.
Since human recombinant thyroid stimulating hormone is not available in China, TSH stimulation requires patients to stop taking thyroxine, which artificially causes hypothyroidism and is more painful for patients. With Elecsys® TgII, post-TSH stimulation Tg testing can be minimized, greatly reducing the patient’s burden.
Calcitonin: a sensitive indicator for the diagnosis and follow-up of medullary thyroid cancer
Calcitonin is secreted by parafollicular cells (C-cells) of the thyroid gland and acts antagonistically with parathyroid hormone secreted by the parathyroid glands to lower serum calcium concentrations, and its secretion is regulated by serum calcium concentrations and gastrin. As a neuroendocrine tumor, medullary thyroid carcinoma ( MTC) is closely associated with Calcitonin, and Dr. Luca Giovanella believes that Calcitonin is very sensitive for screening medullary carcinoma in patients with thyroid nodules, with a higher sensitivity than ultrasound and fine needle biopsy.
He also recommended that basal Calcitonin and carcinoembryonic antigen (CEA) be measured every 6 months during post-MTC follow-up to determine the time to ploidy. If there is a 20-100% increase in Calcitonin or CEA, neck ultrasound is recommended; if Calcitonin is >150 pg/ml, localized imaging of systemic metastases is required.
When performing MTC screening by testing serum Calcitonin, clinical problems such as C-cell hyperplasia, non-MTC thyroid tumors and goiter, and renal failure are often encountered to interfere with the final results. To increase clinical accuracy, experts have given the following advice: Basal or post-stimulation serum Calcitonin levels greater than 100 pg/ml should be interpreted as suspected MTC and require further evaluation and treatment.
In a study using serum Calcitonin and calcitoninogen (PCT) to screen for MTC in patients with thyroid nodules, a pentagastrin stimulation test was performed in 1236 patients with nodules with serum Calcitonin greater than 10 pg/ml, and Calcitonin and PCT were measured after stimulation. Follow-up confirmed that PCT measurement in patients with thyroid nodules with elevated basal Calcitonin significantly improved the accuracy of Calcitonin in diagnosing MTC.
A retrospective multicenter study measured serum Calcitonin levels in patients undergoing fine-needle aspiration biopsy (FNAB). To avoid missing MTC, all suspected patients were required to have FNAB puncture needle rinse fluid Calcitonin measurements. The study confirmed that Calcitonin measurement in the puncture needle rinse is more sensitive than cytological testing for most MTC patients. In addition another test of 839 MTC patients also confirmed that serum Calcitonin was more accurate for MTC detection than ultrasound combined with FNAB.
Serum Calcitonin must also be measured by a validated immunoassay that is calibrated according to the international reference (WHO 2nd IS 89/620). Results using different assays may vary significantly and therefore clinical thyroid discipline physicians and laboratory specialists are strongly advised to carefully evaluate the performance and clinical performance of the Calcitonin test and to draw from their local MTC patient population for results analysis.
Elecsys® Calcitonin has been approved by the CFDA on March 28, 2014 and is now officially available in China. The Elecsys® Calcitonin assay is universal across all cobas platforms and has high batch-to-batch stability, making it more useful for long-term monitoring of MTC patients.