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Letters to the Editor |
1 Department of Nuclear Medicine, PET-CT Center and Thyroid Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
2 Laboratory for Endocrinology and Tumor Markers, University Hospital, "Fondazione Macchi", Varese, Italy
aAddress correspondence to this author at: Department of Nuclear Medicine/PET-CT Center and Thyroid Unit, Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland. Fax 41-0-91-8118250; e-mail luca.giovanella{at}eoc.ch.
To the Editor:
Undetectable serum thyroglobulin (Tg) after thyroid-stimulating hormone (TSH) stimulation is considered the most reliable marker of cure in patients with differentiated thyroid carcinoma (DTC). Interference by Tg antibodies (TgAb) and heterophile antibodies (HAb) may lead to false decreases and increases in Tg concentrations, respectively (1)(2).
A 32-year-old woman with enlarged neck lymph nodes was referred to our center. She had undergone total thyroidectomy and radioiodine treatment 4.2 years before for pT1Nx papillary thyroid carcinoma (PTC). Six months later a neck ultrasound and rhTSH-stimulated Tg assay were negative (stimulated Tg <0.9 µg/L). Subsequently both clinical examination and Tg assay under thyroxine were performed every 12 months, with negative results.
We performed neck ultrasound, which revealed 2 round hypoechoic partially colliquated lymph nodes in the right neck (III level). A fine-needle aspiration biopsy (FNAB) was performed, and the needle-washing fluid was analyzed both by cytological examination and Tg assay (Tg-FNAB). Cytology specimens showed PTC recurrence, and FNAB-Tg was 950.70 µg/L. The serum Tg was undetectable (<0.9 µg/L) with negative TgAb (<60 kU/L), but recovery test results were abnormal (58%, range 80%–120%). The patient underwent modified right-neck dissection, which provided histological confirmation of PTC metastasis in 4 of 34 dissected lymph nodes. The Tg and TgAb measurement and recovery tests were performed on a fully-automated Immulite 2000 (DPC) system. In this case, because of the mismatch between serum and FNAB-Tg concentrations and the low Tg recovery, we further searched for interferences on the serum Tg assay. First, we retested Tg, Tg-recovery, FNAB-Tg, and TgAb using sensitive immunoassays (Tg-plus and Dyno-test Tg, BRAHMS). BRAHMS assay results indicated that Tg was pathologically increased and Tg-recovery was within the reference interval (Table 1
). On the basis of these results we hypothesized that antibodies other than TgAb were causing interference. We then measured serum Tg on the Immulite platform after treating serum samples in a heterophilic blocking tube (Scantibodies Laboratory). After incubation in a heterophilic blocking tube, a Tg increase to 18.2 µg/L was found, confirming interference by HAb leading to a false-negative result.
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TgAb interference is a major pitfall, leading to a falsely low or negative results in approximately 20% of DTC patient sera at the time of cancer diagnosis in the US. The frequency is lower in Europe and declines after thyroidectomy. Use of the TgAb immunometric assay is strongly recommended to screen for interferences in patients with DTC, but the usefulness of the recovery-test is under debate. However, because no consistent correlation pattern has been demonstrated between different Tg and TgAb immunoassays, undetectable TgAb in apparently TgAb-negative sera should be regarded with caution (2). In these cases a recovery test should be considered, especially if Tg testing did not fit the clinical picture(3). In our patient, the low recovery signaled interference on the Tg assay, with increased TgAb undetected by 2 different immunoassays. Generally the HAb binds to both the capture and detection antibody, simulating the presence of analyte in its absence and resulting in a false-positive result or a falsely increased measurement if the analyte is present. Preissner et al.(2) evaluated 1106 serum Tg samples and detected HAb interferences in approximately 3% of the specimens tested, without falsely low or negative results; however, samples with Tg concentrations <1 µg/L were excluded from the study. In some cases, HAb binds only to the capture (or detection) antibody, leading to falsely low or negative analyte measurement results(4). As shown in the present case (for the 1st time, to our knowledge) HAb may also interfere with testing by decreasing the measured Tg, leading to false-negative results. The interfering antibody cannot be differentiated with the blocking tube, but animal immunoglobulins added to serum should be useful. Interestingly, HAb did not significantly interfere with Tg measurement in FNAB washing fluid. Similarly, the Tg-FNAB did not appear to be substantially affected by TgAb, probably because of the very high Tg concentrations in the needle-washing fluids(5).
In conclusion, the Tg assay is a cornerstone in DTC follow-up and management. Tg measurement is significantly limited in TgAb-positive patients, however, and HAb may increase or, as shown here, even decrease the measured Tg. Ultrasound examination is of pivotal importance in the management of DTC neck recurrences, and in this case was supported by FNAB, allowing a definitive diagnosis. Thus effective management of DTC will continue to depend on multidisciplinary collaboration, especially for high-risk or relapsing patients.
Acknowledgments
Grant/funding support: None declared.
Financial disclosures: None declared.
Acknowledgments: We acknowledge Dr. Franco Keller (Laboratory for Immunology, Regional Hospital of Bellinzona, Switzerland) for technical suggestions and criticism.
References
The following articles in journals at HighWire Press have cited this article:
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  A A A Ismail Interference from endogenous antibodies in automated immunoassays: what laboratorians need to know J. Clin. Pathol., August 1, 2009; 62(8): 673 - 678. [Abstract] [Full Text] [PDF]
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P M Clark Laboratory services for thyroglobulin and implications for monitoring of differentiated thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 402 - 406. [Abstract] [Full Text] [PDF]
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 L. J. Kricka Commentary Clin. Chem., July 1, 2008; 54(7): 1245 - 1245. [Full Text] [PDF]
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