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Quantitative Reverse Transcription-Polymerase Chain Reaction of Circulating Thyroglobulin Messenger Ribonucleic Acid for Monitoring Patients with Thyroid Carcinoma¹

Department of Medicine (M.D.R., P.L.B-S., Y.H.S., K.D.B., L.W.), Washington Hospital Center and Medstar Research Institute, Washington, DC 20010; Department of Clinical Investigation (J.S.A., G.L.F., R.M.T.), Walter Reed Army Medical Center, Washington, DC 20307; Department of Medicine (C.A.S., J.S.), University of Southern California, Los Angeles, California 90033; Departments of Medicine (P.W.L.) and Pediatrics (M.A.L.), Johns Hopkins University, Baltimore, Maryland 21205

Address correspondence and requests for reprints to: Matthew D. Ringel, M.D., Co-Director Laboratory of Molecular Endocrinology, Section of Endocrinology, Washington Hospital Center, 110 Irving Street, NW, Room 2A-46B, Washington, DC 20010. E-mail: mxr9{at}mhg.edu

Patients with thyroid cancer are monitored for disease recurrence by measurement of serum thyroglobulin (Tg) and iodine-131 (¹³¹I) scanning. To enhance sensitivity and to circumvent antibodies that interfere with Tg immunoassays, we have developed RT-PCR assays that detect circulating thyroid messenger RNA (mRNA) transcripts. We now report results using a sensitive quantitative Tg mRNA assay (Taqman; ABI, Foster City, CA) in comparison with immunoassay in patients previously treated for thyroid cancer. We evaluated 107 patients: 84 during T₄ therapy, 14 after T₄ withdrawal, and 9 at both time points. All patients had near-total thyroidectomy, and 92% received postoperative ¹³¹I. Serum TSH, Tg protein, and Tg mRNA were measured. Patients were grouped based on most recent ¹³¹I scan or pathologically confirmed disease as having no detectable thyroid tissue (n = 33), thyroid bed uptake (n = 37), cervical/regional adenopathy (n = 21), or distant metastases (n = 16). During T₄ therapy, median (range) Tg mRNA values (pg Tg Eq/µg thyroid RNA) for the groups were 1.5 (0–26.8), 9.4 (0.5–90.0), 15.4 (0.2–92), and 12.4 (1.9–16.6), respectively. Using a value of 3 pg Tg Eq/µg thyroid RNA as cut-point, Tg mRNA was positive in 38% of patients with no uptake, 75% with thyroid bed uptake, 84% with cervical/regional disease, and 94% with distant metastases. The median Tg mRNA value for patients with no uptake was lower than the median values for patients with thyroid bed uptake (P = 0.009) or with detectable thyroid tissue at any site (P = 0.010). Patients with negative ¹³¹I whole body scans were also less likely to have detectable Tg mRNA levels than were patients with thyroid bed uptake (P < 0.001) or any detectable thyroid tissue at any location (P < 0.001). Similar differences between these groups were seen after T₄ withdrawal and for the 23 patients with circulating anti-Tg antibodies, when analyzed separately. Eight of the nine patients studied with low and high TSH concentrations displayed greater amounts of circulating Tg mRNA after T₄ withdrawal. In three patients followed prospectively, the amount Tg mRNA correlated with the presence and absence of cervical metastases. In conclusion, we have demonstrated that a quantitative Tg mRNA assay can identify thyroid cancer patients with recurrent or residual thyroid tissue with greater sensitivity and similar specificity to Tg immunoassay during T₄ therapy. The assay was unaffected by anti-Tg antibodies, responded to TSH-stimulation, and was reduced after surgical removal of metastases. These data suggest that this quantitative Tg mRNA assay may be a sensitive marker of tumor recurrence or response to therapy, particularly in patients with anti-Tg antibodies.

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