Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment

Carvalho, Andre Ywata de; Kohler, Hugo Fontan; Carvalho, Camila C. G. Ywata de; Vartanian, Jose Guilherme; Kowalski, Luiz Paulo

doi:10.20945/2359-4292-2022-0506

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Archives of Endocrinology and Metabolism

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Original Article • Arch. Endocrinol. Metab. 68 • 2024 • https://doi.org/10.20945/2359-4292-2022-0506 copy

Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification).

Subjects and methods:

We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy.

Results:

After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-risk to high-risk patients with postoperative s-Tg ≥ 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification.

Conclusions:

The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based on dynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

Keywords
Thyroid; papillary thyroid carcinoma; recurrence; risk assessment, thyroglobulin

Characteristics			N patients
Sex	Female	76.1%	1,226
Age (years):	Mean (range)	43.7 (7-83)	1,611
Tumor size (mm):	Mean (range)	12.8 (0.4-140)	1,611
	≤10 mm	54.7%	881
Aggressive histology		4.3%	70
Multifocality		40.3%	649
Bilaterality		29.2%	471
Extrathyroidal extension	No	72.9%	1,174
	Minor	20.7%	334
	Gross	6.4%	103
Lymphovascular invasion		2%	33
Lymph node metastasis	cN1	12.8%	206
	pN0	3.6%	58
	pN1a	15.9%	256
	pN1b	6.3%	102
Chronic lymphocytic thyroiditis		20.8%	335
ATA risk stratification category	Low	57.8%	932
	Intermediate	35.7%	575
	High	6.5%	104
Neck lymph node dissection	No	79.7%	1,284
	Central (level VI)	13.8%	223
	Central plus lateral (II-VI)	6.5%	104
RAI ablation	Yes	87.3%	1,407
	Mean (range)	135 (30-389.5)
Postoperative s-Tg	Mean (SD)	27.3 (368.4)
	Median (range)	2.5 (<0.2-10,333)
	≤1 ng/mL	30.4%	489
	1-10 ng/mL	51.1%	823
	≥10 ng/mL	18.5%	299
Clinical response to initial therapy classification	Complete	80.1%	1,291
	Biochemical incomplete	4%	64
	Structural incomplete	2.7%	43
	Indeterminate	13.2%	213
Follow-up (years)	Mean (range)	61.5 (12-246)
Recurrence	Total	6.1%	99
	During the first 2 years	60.6%	60
	3-5 years	28.3%	28
	After 5 years	11.1%	11

		Univariate Analysis		Multivariate Analysis
		HR (95% CI)^* * HR and 95% CI estimated by Cox regression models.	P value^ P value calculated using the log-rank test.	HR (95% CI)^* * HR and 95% CI estimated by Cox regression models.	P value^ P value calculated using the log-rank test.
Male sex		1.81 (1.20-2.75)	0.005	1.23 (0.80-1.91)	0.347
Age < 55 years		0.66 (0.37-1.16)	0.146
Tumor size > 10 mm		2.20 (1.47-3.31)	<0.001	1.09 (0.69-1.71)	0.715
Multifocality		1.14 (0.76-1.70)	0.526
Bilaterality		1.49 (0.99-2.24)	0.057
Chronic thyroiditis		0.64 (0.38-1.07)	0.089
ATA risk category	Low	1		1
	Intermediate	5.19 (3.12-8.63)	<0.001	3.07 (1.81-5.19)	<0.001
	High	11.01 (6.18-19.16)	<0.001	4.46 (2.32-8.57)	<0.001
Postoperative s-Tg level (ng/mL)	<1	1		1
	1-10	2.10 (0.89-4.95)	0.089	1.99 (0.83-4.74)	0.121
	≥10	16.25 (7.47-35.32)	<0.001	10.67 (4.8-23.6)	<0.001

		n (%)	5-year RFS %	Univariate Analysis
		n (%)	5-year RFS %	HR^* * HR and 95% CI estimated by Cox regression models. (95% CI)	P value^ P value calculated using the log-rank test.
	Total	1,611 (100)	93.4
ATA risk	Low	932 (57.8)	97.7	1.0 (ref.)
	Intermediate	575 (35.7)	89.5	4.46 (2.68-7.41)	<0.001
	High	104 (6.5)	73.8	12.74 (7.16-22.65)	<0.001
Postoperative s-Tg (ng/mL)	<10	1,311 (81.4)	97.9	1.0 (ref.)
	≥10	300 (18.6)	74.3	12.24 (7.90-18.96)	<0.001
ATA risk and s-Tg (ng/mL)	Low/<10	815 (50.6)	99.1	1.0 (ref.)
	Low/≥10	117 (7.3)	88.5	9.79 (4.13-23.25)	<0.001
	Intermediate/<10	433 (26.9)	96.4	2.77 (1.17-6.58)	0.021
	Intermediate/≥10	142 (8.8)	70.4	29.62 (14.36-61.08)	<0.001
	High/<10	63 (3.9)	91.2	10.6 (3.95-28.47)	<0.001
	High/≥10	41 (2.5)	48.0	57.29 (25.88-126.8)	<0.001

		Initial estimate of risk of recurrence	Dynamic risk stratification
		Initial estimate of risk of recurrence	Complete response	Indeterminate response	Incomplete response
ATA risk	Low	2.3% (21/932)	0.5% (4/806)	3.1% (3/97)	48.3% (14/29)
	Intermediate	9% (52/575)	1.2% (5/428)	14.6% (13/89)	58.6% (34/58)
	High	25% (26/104)	5.3% (3/57)	22.2% (6/27)	85% (17/20)
s-Tg (ng/mL)	<10	2.1% (28/1,312)	0.6% (7/1,153)	5.3% (7/132)	51.9% (14/27)
	≥10	23.7% (71/299)	3.6% (5/138)	18.5% (15/81)	63.8% (51/80)
ATA risk/postoperative s-Tg (ng/mL)	Low/<10	1.1% (9/815)	0.3% (2/736)	1.5% (1/69)	60% (6/10)
	Low/≥10	10.3% (12/117)	2.9% (2/70)	7.1% (2/28)	42.1% (8/19)
	Intermediate/<10	2.8% (12/433)	0.8% (3/368)	7.7% (4/52)	38.5% (5/13)
	Intermediate/≥10	28.2% (40/142)	3.3% (2/60)	24.3% (9/37)	64.4% (29/45)
	High/<10	11.1% (7/63)	4.2% (2/48)	18.2% (2/11)	75% (3/4)
	High/≥10	46.3% (19/41)	11.1% (1/9)	25% (4/16)	87.5% (14/16)

Variable	Category	n (%)	PVE	Odds ratio (95% CI)	P value
ATA risk	Low	932 (57.8)	0.127	1.0 (ref.)
	Intermediate	575 (35.7)		4.31 (2.57-7.24)	<0.001
	High	104 (6.5)		14.46 (7.78-26.87)	<0.001
Postoperative s-Tg (ng/mL)	<10	1,311 (81.4)	0.233	1.0 (ref.)
	≥10	300 (18.6)		14.21 (8.97-22.49)	<0.001
ATA risk/postoperative s-Tg (ng/mL)	Low/<10	815 (50.6)	0.299	1.0 (ref.)
	Low/≥10	117 (7.3)		10.23 (4.21-24.87)	<0.001
	Intermediate/<10	433 (26.9)		2.55 (1.07-6.11)	0.035
	Intermediate/≥10	142 (8.8)		35.12 (16.56-74.49)	<0.001
	High/<10	63 (3.9)		11.19 (4.02-31.17)	<0.001
	High/≥10	41 (2.5)		77.34 (31.47-190.1)	<0.001
Response to treatment	Excellent	1,291 (80.1)	0.491	1.0 (ref.)
	Indeterminate	213 (13.2)		12.28 (5.98-25.21)	<0.001
	Incomplete	107 (6.6)		164.95 (82.9-328.3)	<0.001

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[1] Correspondence to: Andre Ywata de Carvalho A.C. Camargo Cancer Center, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia Rua Professor Antônio Prudente, 211 01509-010, São Paulo, SP, Brasil andreywata@bol.com.br