THYROIDVolume 15, Number 9, 2005© Mary Ann Liebert, Inc.

Presurgical Serum Thyroglobulin Has No Prognostic Valuein Papillary Thyroid Cancer

Elisa Guarino, Bianca Tarantini, Tania Pilli, Serenella Checchi, Lucia Brilli, Cristina Ciuoli, Giovanni Di Cairano, Paola Mazzucato, and Furio Pacini

We investigated whether serum thyroglobulin determination before surgery for differentiated thyroid carci-noma may have any prognostic value with regard to tumour extension and disease outcome in a retrospectiveseries of 71 patients with papillary thyroid cancer. Presurgical serum thyroglobulin levels were correlated withthe size of the primary tumoral nodule (p � 0.006) and of the whole thyroid (p � 0.02). The same correlationwas found in a control group of patients with benign thyroid nodules, confirming that presurgical serum thy-roglobulin cannot be used for the differential diagnosis of thyroid carcinoma. Presurgical serum thyroglobulinlevels did not differ among patients with tumor limited to thyroid gland or extending to cervical lymph nodesor invading outside the thyroid capsule or metastasising to distant size. In addition presurgical serum thy-roglobulin levels were not correlated with the disease outcome after a mean follow-up of 9 years: no differencewas found among patients in complete remission or with persistent disease or dead from thyroid cancer. Inconclusion, this study failed to show any prognostic value of presurgical serum thyroglobulin determinationthat consequently should not be measured.

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Introduction

SERUM THYROGLOBULIN (Tg) is a specific and sensitivemarker to detect recurrent and persistent disease during

the follow-up of patients with differentiated thyroid carci-noma after total thyroidectomy and 131-iodine (131I) treat-ment (1). Serum Tg levels are not useful to differentiate be-nign and malignant thyroid nodules before thyroidectomy,because of the high and overlapping Tg concentrations foundin any thyroid disorder associated with increased thyroidvolume or function (1–3). On the contrary, after total thy-roidectomy serum Tg levels are usually detectable or ele-vated in most patients with persistent or recurrent diseasewhen studied under exogenous (recombinant human thy-rotropin [rhTSH]) (4) or endogenous TSH stimulation (5). Inthis situation a gross correlation has been found between re-sidual tumour and serum Tg concentrations (6), suggestingthat the higher serum Tg levels the larger is the tumour bur-den.

The present retrospective study was aimed at investigat-ing the origin of Tg production in malignant and benign thy-roid nodules and to assess whether serum Tg determinationbefore surgery for thyroid cancer has any prognostic valuewith regard to the extent of disease and its outcome. To thispurpose we studied serum Tg concentration in patients withbenign nodules and, before surgery, in a group of patients

undergoing treatment for papillary thyroid cancer. In the lastgroup the results were correlated with the tumour burdenand the outcome of the disease.

Patients and Methods

Patients

Of 172 patients treated in our institution in the last 20 yearsfor papillary thyroid carcinoma we selected all patients (n �71; 41%) who had serum Tg determination performed beforesurgery. Other selection criteria were absence of anti-Tg an-tibodies, no abnormality of thyroid function and no thyroidspecific treatment.

There were 54 females and 17 males, ranging in age from7–81 years at diagnosis (mean, 44 � 18 years). The follow-upfrom initial surgery to inclusion in our study ranged from1–20 years (mean 9 � 6.7 years). All patients were treatedwith near-total thyroidectomy and 131I thyroid ablation. Thesubsequent follow-up was based on periodic serum Tg de-termination and 131I whole-body scan (WBS) in hypothyroidstate and neck ultrasonography. Additional treatments in-cluded 131I therapy for local or distant metastases and sur-gical procedures when indicated.

As control group we selected 34 patients with solitary thy-roid nodules, benign at fine-needle aspiration cytology, who

Department of Internal Medicine, Endocrinology and Metabolism, Section of Endocrinology and Metabolism, University of Siena, Italy.

were not taking thyroid medication and had normal thyroidfunction. They were 25 females and 9 males, ranging in agefrom 25–87 years at diagnosis (mean 60 � 15 years).

Methods

Serum Tg was measured by immunoradiometric assay(Brahams, Aktiengesellschaft D-16761 Hennigsdorf) with afunctional sensitivity of 3 ng/mL until 1995 and chemilu-minescent assay (Immulite 2000 Tg, DPC Diagnostic Prod-ucts Corporation, Los Angeles, CA) with a functional sensi-tivity of 1 ng/mL thereafter.

Anti-Tg antibodies were determined by chemiluminescentassay (EURO/DPC Limited Llanberis, Gwynedd, United

Kingdom): an anti-Tg level of less than 20 U/mL (corre-sponding to the functional sensitivity of the assay) was con-sidered negative.

Presurgical serum Tg concentrations were correlated withpresurgical TSH levels, thyroid and tumor size as assessedby ultrasonography, clinical class (according to the classifi-cation proposed by De Groot et al. [7], and outcome of dis-ease.

In the control group Tg concentrations were correlatedwith TSH levels, thyroid, and nodule size. Thyroid and nod-ule volumes were assessed by neck ultrasonography usinga colour Doppler apparatus (Technos MP, Esaote Biomedica,Firenze, Italy) with a 7.5-MHz linear transducer. To obtainthe volume, the three diameters of both lobes were measuredand the total volume was calculated according to the ellip-soid model (width � length � thickness � 0.52 for eachlobe) as previously described (8).

Statistical analysis

Comparison between groups was performed by Mann-Whitney U test and correlation analysis by Spearman corre-lation coefficient using the GraphPad Prism version 3.0.

Results

All patients had classical papillary thyroid tumour. Thesize of the primary tumour ranged between 0.2–7 cm (mean,2.2 � 1.3 cm; median 2 cm). In case of multinodular goiterwhen the malignant nodule was not the largest one (4 cases)the size of the largest benign nodule was also considered forstatistical analysis.

According to the clinical, surgical and pathological find-ings integrated with the results of posttherapy (for ablation)131I WBS, 40 patients were classified as class I (intrathyroidal

GUARINO ET AL.1042

FIG. 1. Individual values of serum thyroglobulin (Tg) inpatients with thyroid cancer before surgery and in patientswith benign thyroid nodules: the horizontal bar representsthe mean � standard deviation (SD).

FIG. 2. Correlation between presurgical thyroglobulin (Tg) levels in thyroid cancer patients and size of the largest nod-ule (A). The same correlation for patient with benign nodule is shown in (B). Log scale in x axis.

tumor), 22 patients as class II (lymph node metastases), 5 pa-tients as class III (extrathyroidal tumor with or withoutlymph node metastases), and 4 patients as class IV (distantmetastases). According to the outcome of disease at the endof follow-up, 59 patients were completely cured, 11 patientshad persistent disease, and 1 died of thyroid cancer.

In the control group the size of nodule ranged from 1 to7.5 cm (mean, 3.2 � 1.8 cm; median, 2.7 cm).

In patients with thyroid cancer mean presurgical serumTg values were 282 � 501 ng/mL (range, 7.6–2667 ng/mL)and mean serum TSH at the same time was 1.5 � 0.9 �U/mL(range, 0.2–4.4 �U/mL). In control patients mean serum Tgwas 85.1 � 100 ng/mL (median, 44.7 ng/mL; range, 6.2–432ng/mL) and mean serum TSH was 1.2 � 0.8 �U/mL (me-dian 1.0 �U/mL; range, 0.4–3.2 �U/mL). In both malignant

and benign nodules, no correlation was found betweenpresurgical serum Tg concentrations and serum TSH.

As shown in Figure 1, mean serum Tg was significantlyhigher in patients with thyroid cancer compared to controlpatients (p � 0.04). However, there was a great overlap of in-dividual serum Tg values among the two groups.

As shown in Figure 2, a significant correlation was foundbetween pre-surgical serum Tg levels in thyroid cancer pa-tients and size of the largest nodule (p � 0.006); also in be-nign nodules a positive correlation between serum Tg andnodules size was found (p � 0.002).

Serum Tg was positively correlated with thyroid volumeassessed by ultrasonography in both patients with thyroidcancer and patients with benign nodules (p � 0.02 and p �0.03, respectively) (Fig. 3). In patients with thyroid cancer,

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FIG. 3. Correlation between thyroid volume by ultrasound and presurgical thyroglobulin (Tg) levels in thyroid cancer pa-tients (A) and in patients with benign nodules (B). This analysis was available in 18 and 34 patients, respectively.

FIG. 4. Individual presurgical serum thyroglobulin (Tg) concentrations according to the clinical class. Bars represent themean.

mean serum Tg concentrations were not different among thevarious clinical classes (Fig. 4): mean presurgical serum Tg concentrations were 360 � 621 ng/mL (range, 9–2667ng/mL) in class I patients, mean Tg 151 � 268 ng/mL (range,9–1276 ng/mL) in class II patient, mean Tg 153 � 182.1ng/mL (range, 8–460 ng/mL) in class III patients, and meanTg 381 � 207 ng/mL (range, 113–598 ng/mL) in class IV pa-tients.

No difference in pre-surgical serum Tg concentrations wasfound according to the final outcome of the disease (Fig. 5).Mean presurgical serum Tg concentrations were 265.6 � 488ng/mL (range, 3–2667 ng/mL) in cured patients, mean Tg350 � 448 ng/mL (range, 26–1760 ng/mL) in patients withpersistent disease and 8 ng/mL in the one patient who died.

Discussion

This retrospective study confirms that measurement ofserum Tg levels in patients with thyroid nodules cannot beused to differentiate the benign or malignant nature of thenodule. Although mean serum Tg levels were significantlyhigher in malignant nodules, individual values overlappedwith those of benign nodules in more than 80% of the cases,and were not correlated with serum TSH levels. In both be-nign and malignant nodules, serum Tg levels were posi-tively correlated with the size of the nodule and with thesize of the whole thyroid, assessed by ultrasonography.Thus it is not possible from our data to quantify the rela-tive contribution of thyroid nodules and normal thyroid tothe serum Tg concentration. Because thyroglobulin is pres-ent in normal thyroid cells as well as in benign ad malig-nant thyroid cells (as demonstrated by Tg immunohisto-chemistry and by direct measurement of Tg in fine-needleaspiration cytology) it is conceivable that any thyroid nod-ule of follicular origin is able not only to produce Tg butalso to release it in the circulation. Unfortunately, it is notpossible to ascertain differences in Tg secretion rate be-tween normal thyroid tissue, benign nodules, and thyroidcancer. Similarly unknown it is the intimate mechanism ofTg secretion from thyroid nodule, whether it is an activeprocess similar to that specific of normal thyroid cells orthe result of likeage from disrupted intercellular connec-tions, as reported by Van Herle et al. (9,10). It is also of in-terest that mean serum Tg levels in patients with thyroidnodules are usually higher compared to normal subjects

without thyroid disorders (2,3). One possible explanationfor this finding may be that thyroid nodules, particularlywhen of large volume, may exert compression on the sur-rounding normal thyroid resulting in increased release ofTg in the circulation (11).

It is well known that after surgery and thyroid ablationfor thyroid cancer serum Tg measurement is the most spe-cific and sensitive marker for the identification of persistentor recurrent disease (1,2,4,5) and that there is a gross corre-lation between serum Tg and tumor mass (6). To our knowl-edge, no study has addressed whether serum Tg levels im-mediately before surgery might have prognostic implicationwith regard to the post-surgical outcome. Our results indi-cate that before surgery serum Tg measurement have noprognostic indication, as shown by the lack of correlationwith tumour stage and outcome of disease.

In conclusion our study suggests that serum Tg should notbe measured in the diagnostic evaluation of thyroid nodules.

Acknowledgments

The study was supported in part by grants from: Minis-tero dell’Istruzione, Università e Ricerca Scientifica (MIUR,Italy) 2003 and Associazione Italiana per la Ricerca sul Can-cro (AIRC 2003), Italy.

References

1. Pacini F, Pinchera A 1999 Serum and tissue thyroglob-ulin measurement: Clinical applications in thyroid disease.Biochimie 81:463–467.

2. Pacini F, Pinchera A, Giani C, Grasso L, Doveri F, BaschieriL 1980 Serum thyroglobulin in thyroid carcinoma and otherthyroid disorders. J Endocrinol Invest 3:283–292.

3. Schneider AB, Favus MJ, Stachura ME 1977 Plasma thy-roglobulin in detecting thyroid carcinoma after childhoodhead and neck irradiation. Ann Intern Med 86:29–34.

4. Haugen BR, Pacini F, Reiners C, Schlumberger M, LadensonPW, Sherman SI, Cooper DS, Graham KE, Braverman LE,Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, DanielsGH, Ross DS, Luster M, Samuels MH, Becker DV, MaxonHR 3rd, Cavalieri RR, Spencer CA, McEllin K, WeintraubBD, Ridgway EC 1999 A comparison of recombinant humanthyrotropin and thyroid hormone withdrawal for the de-tection of thyroid remnant or cancer. J Clin EndocrinolMetab 84:3877–3885.

5. Pacini F, Lari R, Mazzeo S, Grasso L, Taddei D, Pinchera A:1985 Diagnostic value of a single serum thyroglobulin de-termination on and off thyroid suppressive therapy in thefollow-up of patients with differentiated thyroid cancer. ClinEndocrinol (Oxf) 23:405–409.

6. Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M, Bel-lon N, Caillou B, Travagli JP, Schlumberger M 2002 Rela-tionship between tumor burden and serum thyroglobulinlevel in patients with papillary and follicular thyroid carci-noma. Thyroid 12:707–711.

7. DeGroot LJ, Kaplan EL, McCormick M, Straus FH 1990 Nat-ural history, treatment and course of papillary thyroid car-cinoma. J Clin Endocrinol Metab 71:414–424.

8. Vitti P, Martini E, Aghini-Lombardi F, Rago T, AntonangeliL, Maccheroni D, Nanni P, Loviselli A, Balestrieri A, Ara-neo G 1994 Thyroid volume measurement by ultrasound inchildren as a tool for the assessement of mild iodine defi-ciency. J Clin Endocrinol Metab 79:600–603.

9. Van Herle AJ, Vassart G, Dumont JE 1979 Control of thy-

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FIG. 5. Individual presurgical serum thyroglobulin (Tg)concentrations according to final outcome. Bars represent themean.

roglobulin synthesis and secretion (First of two parts). NEngl J Med 301:239–249.

10. Van Herle AJ, Vassart G, Dumont JE 1979 Control of thy-roglobulin synthesis and secretion (second of two parts). NEngl J Med 301:307–314.

11. Lever EG, Refetoff S, Scherberg NH, Carr K 1983 The influ-ence of percutaneous fine needle aspiration on serum thy-roglobulin. J Clin Endocrinol Metab 56:26–29.

Address reprint requests to:F. Pacini, M.D.

Section of Endocrinology and MetabolismUniversity of Siena

Italy

E-mail: pacini8@unisi.it

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