Table 4.
Studies of Thyroglobulin Testing—Results
| Study, year | Outcome | Outcome prevalence | Tg threshold | Sensitivity | Specificity | Positive predictive value | Negative predictive value | Comments |
|---|---|---|---|---|---|---|---|---|
| Tg testing following partial thyroidectomy | ||||||||
| Alzahrani, 2002 (7) | (a) Residual thyroid cancer | (a) 39% (39/100) | >20 ng/mL | (a) 0.44 (17/39) | (a) 0.79 (48/61) | (a) 0.57 (17/30) | (a) 0.69 (48/70) | None |
| (b) Cervical lymph node metastasis | (b) 40% (36/90) | (b) 0.47 (17/36) | (b) 0.80 (43/54) | (b) 0.61 (17/28) | (b) 0.69 (43/62) | |||
| Park, 2018 (30) | Recurrent/persistent disease | 8.5% (19/223) | (a) ≥20% increase | (a) 0.74 (14/19) | (a) 0.08 (16/204) | (a) 0.07 (14/202) | (a) 0.76 (16/21) | None |
| (b) ≥50% increase | (b) 0.47 (9/19) | (b) 0.38 (79/204) | (b) 0.07 (9/134) | (b) 0.89 (79/89) | ||||
| (c) ≥100% increase | (c) 0.26 (5/19) | (c) 0.75 (153/204) | (c) 0.09 (5/56) | (c) 0.92 (153/167) | ||||
| Ritter, 2020 (33) | Recurrence | 7.2% (12/167) | Not reported | Not reported | Not reported | Not reported | Not reported | Mean Tg 1 level after lobectomy 22.5 ng/mL in 11 of 12 patients with recurrence; 1-year Tg levels did not differ between recurrence and nonrecurrence groups (22.5 vs. 11.3, p = 0.16); at 2 years 3 of 6 patients with recurrence had rising Tg levels |
| Vaisman, 2013 (39) | Recurrence | 7.1% (5/70) | “Rising” Tg, not defined | 0.80 (4/5) | 0.80 (52/65) | 0.24 (4/17) | 0.98 (52/53) | Minor data discrepancy present (study reports 14 false-positive patients which would result in specificity of 0.78 (51/65) rather than 0.80 as reported in study) |
| Tg testing following total or near-total thyroidectomy without RAI therapy | ||||||||
| Durante, 2012 (9) | Recurrent/persistent tumor | 0.3% (1/290) | >1.0 ng/mL on final TSH | Not reported (only 1 case) | Not reported (only 1 case) | Not reported | Not reported | 97.9% (274/280) had final Tg ≤1 ng/mL |
| Janovsky, 2016 (14) | Positive 123I total body scan or neck US | 0% (0/57) | >1 ng/mL | Not reported (no cases) | 0.95 (54/57) | Not reported | Not reported | Mean Tg level at 18 months 0.28 ng/mL. No cases of tumor recurrence observed; Tg levels stable or decreasing throughout follow-up |
| Matrone, 2020 (24) | Recurrence | 0% (0/271) | Not specified | Not reported (no cases) | Not reported (no cases) | Not reported | Not reported | Tg levels were stable in 78%, 60%, and 51% of patients with first postoperative Tg <0.2 ng/mL, 0.2–1 ng/mL, and >1 ng/mL, respectively |
| Nascimento, 2013 (27) | Recurrence | 1.2% (1/86) | Not specified | Not reported (1 case) | Not reported (1 case) | Not reported | Not reported | 1 patient with recurrent disease at 7 months had Tg level of 11 ng/mL |
| van Wyngaarden, 1997 (40) | Not reported | Not reported | Not applicable | Not reported | Not reported | Not reported | Not reported | Subtotal or near-total thyroidectomy: Tg consistently undetectable in 62% and <5 ng/mL in 85% Lobectomy: Tg undetectable in 12% and <5 ng/mL in 25% In patients with higher Tg values, levels remained constant within narrow range provided TSH was not high |
| Postoperative thyroglobulin testing before RAI therapy | ||||||||
| Caballero-Calabuig, 2008 (8) | Thyroid remnant, positive lymph nodes, or metastatic disease | 100% (128/128) | >3 ng/mL (1998–2000); >1.5 ng/mL (2001–2003); >0.5 ng/mL (2004–2005) | 0.90 (115/128) | No noncases | Not calculable | Not calculable | None |
| Giovanella, 2008 (10) | Positive 131I total body scan | Not reported | >1.10 ng/mL | 0.83 (n/N not reported) | 0.66 (n/N not reported) | Not calculable | Not calculable | None |
| Grunwald, 1996 (11) | (a) Lymph node metastases | (a) 12% (11/92) | >6 ng/mL | (a) 0.27 (3/11) | (a) 1.0 (81/81) | (a) 1.0 (3/3) | (a) 0.91 (81/89) | Threshold not prespecified |
| (b) Distant metastases | (b) 12% (11/92) | (b) 0.73 (8/11) | (b) 1.0 (81/81) | (b) 1.0 (8/8) | (b) 0.96 (81/84) | |||
| (c) Recurrence | (c) 9.0% (8/89) | (c) 0.38 (3/8) | (c) 1.0 (81/81) | (c) 1.0 (3/3) | (c) 0.94 (81/86) | |||
| Hasbek, 2014 (12) | (a) Positive 131I total body scan | (a) 5.9% (13/221) | (a) >10 ng/mL | (a1) 0.69 (9/13) (b1) 0.92 (11/13) |
(a1) 0.66 (138/208) | (a1) 0.11 (9/79) |
(a1) 0.97 (138/142) |
3.6% of patients had aggressive tumor subtypes |
| (b) Distant or lymph node metastases on 131I total body scan | (b) 5.0% (11/221) | (b) >2 ng/mL | (a2): 0.82 (9/11) (b2): 0.91 (10/11) |
(b1) 0.35 (73/2080 | (b1) 0.08 (11/146) | (b1) 0.97 (73/75) | ||
| Heemstra, 2007 (13) | (a) Tumor presence | (a) 14.9% (33/222) | >27.5 ng/mL | (a) 0.88 (29/33) | (a) 0.90 (171/189) | (a) 0.62 (29/47) | (a) 0.38 (18/48) | None |
| (b) Distant metastases | (b) 9.5% (21/222) | (b) 0.86 (18/21) | (b) 0.85 (171/201) | (b) 0.98 (171/175) | (b) 0.98 (171/174) | |||
| Kim, 2013 (15) | Recurrence | 3.2% (among those with biochemical remission) | >5.3 ng/mL | Not reported | Not reported | Not reported | Not reported | AUROC 0.87 (CI not reported); adjusted OR 36.14 [CI 7.48–174.60] Change in stimulated Tg around time of ablation did not predict recurrence |
| Kim, 2005 (16) | Recurrence | 13.0% (35/268) | (a) >10 ng/mL | (a) 0.77 (27/35) | (a) 0.84 (196/233) | (a) 0.42 (27/64) | (a) 0.96 (196/204) | None |
| (b) >2 ng/mL | (b) 0.94 (33/35) | (b) 0.53 (123/233) | (b) 0.23 (33/143) | (b) 0.98 (123/125) | ||||
| Krajewska, 2016 (17) | Relapse or progression | 9.4% (48/510) | >30 ng/mL | 0.50 (24/48) | 0.92 (37/462) | 0.05 (24/449) | 0.61 (37/61) | Discrepancy between reported diagnostic accuracy and data reported in study; diagnostic accuracy calculated from data in study |
| Latrofa, 2016 (18) | Metastatic disease (distant or lymph node) | 5.6% (10/177); 1.7% (3/177) distant and 4.0% (7/177) lymph node | Detectable | 0.80 (8/10) | Not reported | Not reported | Not reported | Both patients with undetectable Tg and metastatic disease had positive TgAb |
| Ledwon, 2021 (19) | Recurrence | 6.6% (43/650) | >0.7 ng/mL | 0.54 (23/43) | 0.76 (461/607) | 0.14 (23/169) | 0.96 (461/481) | Stimulated pre-RAI Tg was not predictive of recurrence (diagnostic accuracy not reported) |
| Lima, 2002 (20) | Metastatic disease (distant or lymph node) | 52.4% (22/42); 14.3% (6/42) distant and 38.1% (16/42) lymph node | >2.3 ng/mL | 0.73 (16/22) | 0.95 (19/20) | 0.94 (16/17) | 0.76 (19/25) | Discrepancy between reported diagnostic accuracy and data reported in study; diagnostic accuracy calculated from data in study |
| Lin, 2011 (21) | Distant metastatic disease | 19.3% (47/244) | Not reported | Not reported | Tg: 0.913 [CI 0.85–0.97] | Not reported | Not reported | None |
| Tg/TSH ratio: 0.92 [CI 0.86–0.97] | ||||||||
| Makarewicz, 2006 (22) | Metastatic disease or recurrence | 18.0% (32/178); 10.1% (18/178) distant and 11.2% (20/178) lymph node | Not reported | Not reported | Not reported | Not reported | Not reported | AUROC: 0.77 (0.66–0.89) |
| Makarewicz, 2006 (23) | Metastatic disease (distant or lymph node) or recurrence | 14.2% (35/247); 7.3% (18/247) lymph node (no. of patients with distant metastases unclear) | >38.1 ng/mL | 0.57 (20/35) | 0.96 (204/212) | 0.09 (20/232) | 0.93 (204/219) | None |
| Matrone, 2017 (25) | Metastatic disease (distant or lymph node) | 5.3% (27/505); 0.8% (4/505) distant and 4.6% (23/505) lymph node | >2 ng/mL | 0.41 (11/27) | 0.88 (421/478) | 0.16 (11/68) | 0.96 (421/437) | None |
| Matthews, 2016 (26) | Recurrence | 11.0% (11/100) | >3 ng/mL | 1.0 (11/11) | 0.55 (49/89) | 0.22 (11/51) | 1.00 (49/49) | Positive predictive value for Tg >27.5 μg/L 0.31 [CI 0.11–0.59]; OR 4.50 [CI 1.35–15.04] |
| Ng, 2000 (28) | Thyroid remnant, positive lymph nodes, or metastatic disease | (a) 58.3% (210/360) | ≥30 ng/mL | (a) 0.46 (97/210) | (a) 0.97 (146/150) | (a) 0.96 (97/101) | (a) 0.56 (146/259) | (a) Reference standard 131I whole body scan |
| (b) 45.3% (163/360) | (b) 0.50 (81/163) | (b) 0.90 (177/197) | (b) 0.80 (81/101) | (b) 0.68 (177/259) | (b) Reference standard 99mTc-sestamibi scan | |||
| Oyen, 2000 (29) | Distant metastatic disease | 9.8% (25/254) | ≥0.78 ng/mL (≥10 pmol/L) | 1.00 (25/25) | 0.42 (96/229) | 0.16 (25/158) | 1.0 (96/96) | None |
| Polachek, 2011 (31) | Persistent disease (active disease [structural disease on imaging or detectable suppressed Tg] within 1 year of treatment) | 25.0% (105/420) | (a) >10 ng/mL | (a) 0.73 (77/105) | (a) 0.73 (230/315) | (a) 0.48 (77/162) | (a) 0.89 (230/258) | Model with sex, lymph nodes, distant metastasis, tumor invasion, tumor size, and baseline Tg <10 ng/mL associated with sensitivity of 0.80 and specificity of 0.68 |
| (b) >2.5 ng/mL | (b) 0.90 (94/105) | (b) 0.42 (132/315) | (b) 0.66 (94/277) | (b) 0.92 (132/143) | ||||
| Prabhu, 2018 (43) | Metastatic disease (distant or lymph node) | 12.0% (12/100); 10.0% (10/100) lymph node and 4.0% (4/100) distant | (a) ≥1 ng/mL | (a) 1.00 (12/12) | (a) 0.24 (22/90) | (a) 0.15 (12/80) | (a) 1.00 (22/22) | None |
| (b) ≥2 ng/mL | (b) 0.92 (11/12) | (b) 0.37 (33/90) | (b) 0.19 (11/58) | (b) 0.97 (33/34) | ||||
| (c) >5 ng/mL | (c) 0.83 (10/12) | (c) 0.57 (51/90) | (c) 0.20 (10/49) | (c) 0.96 (51/53) | ||||
| Ren, 2021 (32) | Metastatic disease (distant or lymph node) | 85.5% (201/235); 19.6% (46/235) distant and 66.0% (155/235) lymph node | (a) >61.87 ng/mL (distant metastasis) | (a) 0.98 (45/46) | (a) 0.88 (30/34) | (a) 0.92 (45/49) | (a) 0.97 (30/31) | (a) AUROC 0.96 [CI 0.93–0.99] |
| (b) >32.13 ng/mL (lymph node metastasis) | (b) 0.19 (29/155) | (b) 0.71 (24/34) | (b) 0.74 (29/39) | (b) 0.16 (24/150) | (b) AUROC 0.57 [CI 0.45–0.69] | |||
| Ronga, 1999 (34) | Metastatic disease (distant or lymph node) | 23.7% (79/334); 9.6% (32/334) distant and 14.1% (47/334) | (a) >30.25 ng/mL | (a) 0.84 (66/79) | (a) 0.86 (219/255) | (a) 0.65 (66/102) | (a) 0.94 (219/232) | None |
| (b) >11.05 ng/mL | (b) 0.94 (75/79) | (b) 0.54 (138/255) | (b) 0.39 (75/192) | (b) 0.97 (138/142) | ||||
| (c) >2.25 ng/mL | (c) 0.99 (78/79) | (c) 0.10 (26/229) | (c) 0.25 (78/307) | (c) 0.96 (26/27) | ||||
| Rosario, 2011 (35) | Persistent disease | 3.4% (8/237) | (a) >1 ng/mL | (a) 1.0 (8/8) | (a) 0.58 (132/229) | (a) 0.06 (8/140) | (a) 1.0 (97/97) | None |
| (b) >10 ng/mL | (b) 0.50 (4/8) | (b) 0.93 (213/229) | (b) 0.02 (4/217) | (b) 0.80 (16/20) | ||||
| Sjuzo, 2021 (36) | Recurrent or persistent disease | 16% (36/222) | >34.6 ng/mL | 0.83 (29/35) | 0.86 (160/187) | 0.52 (29/56) | 0.96 (160/166) | AUROC 0.82 (SD not reported) |
| Torlontano, 2006 (37) | Persistent nodal disease | 3.8% (3/80) | >1 ng/mL | 0.67 (2/3) | 0.57 (43/77) | 0.06 (2/36) | 0.98 (43/44) | Basal (unstimulated) Tg <1 ng/mL in all patients with nodal disease |
| Toubeau, 2004 (38) | Progression (clinical reappearance after complete ablation) | 9.6% (20/208) | >30 ng/mL | 0.65 (13/20) | 0.91 (171/188) | 0.43 (13/30) | 0.96 (171/178) | Tg >30 ng/mL: Adjusted OR 10.1 [CI 4.0–25.7] for progression (not included in multivariable model that included post iodine therapy variables) |
| Zerva, 2006 (41) | Metastatic disease following RAI therapy (distant or lymph node) | 9.3% (23/248); 7.7% (19/248) distant and 2.8% (7/248) lymph node | (a) Tg >8 ng/mL | (a) 0.91 (21/23) | (a) 0.86 (194/225) | (a) 0.40 (21/52) | (a) 0.99 (194/196) | None |
| (b) Tg/131I uptake >7 ng/mL/% | (b) 0.96 (22/23) | (b) 0.96 (215/225) | (b) 0.69 (22/32) | (b) 0.995 (215/216) | ||||
| Zhao, 2017 (42) | Distant metastatic disease | 22.7% (72/317) | (a) Initial Tg >12.35 ng/mL | (a) 0.90 (65/72) | (a) 0.83 (204/245) | (a) 0.61 (65/106) | (a) 0.97 (204/211) | AUROC (SE) (a) 0.92 (0.02) (b) 0.95 (0.02) (c) For >0, 0.91 (0.02) and for <0, 0.86 (0.08) (d) For >0, 0.91 (0.02) and for <0, 0.90 (0.07) Cutoffs for change in Tg and change in Tg/change in TSH unclear |
| (b) Second Tg >22.10 ng/mL | (b) 0.90 (65/72) | (b) 0.86 (210/245) | (b) 0.65 (65/100) | (b) 0.97 (210/217) | ||||
| (c) Change in Tg 3.90–6.55 ng/mL | (c) 0.89 (64/72) | (c) 0.79 (194/245) | (c) 0.56 (64/115) | (c) 0.96 (194/202) | ||||
| (d) Change in Tg/change in TSH −0.40 to −0.41 ng/mIU | (d) 0.83 (60/72) | (d) 0.90 (221/245) | (d) 0.71 (60/84) | (d) 0.95 (221/233) | ||||
Ab, antibody; AUROC, area under the receiver operating characteristic curve; CI, confidence interval; SD, standard deviation; SE, standard error.