10 1089@thy 2017 0578

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© Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2017.0578
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Intermediate-Risk Papillary Thyroid Cancer: Risk Factors for Early
Recurrence in Patients with Excellent Response to Initial Therapy
This paper has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Augusto Enrique Llamas Olier

Intermediate-Risk Papillary Thyroid Cancer: Risk Factors for Early Recurrence in Patients with Excellent Response to Initial Therapy (DOI: 10.1089/thy.2017.0578)
Médico. Especialista en Medicina Nuclear
Grupo de Medicina Nuclear. Instituto Nacional de Cancerología.
Calle 1 # 9-85 Bogotá D.C. Colombia

Downloaded by KAOHSIUNG MEDICA UNIVERSITY from www.liebertpub.com at 09/06/18. For personal use only.
Tel: 5713340978
allamas@cancer.gov.co
Diana Isabel Cuéllar Rivera
Bacterióloga. MSc en Epidemiología

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Grupo de Investigación Epidemiológica del Cáncer. Instituto Nacional de Cancerología.
Calle 1 # 9-85 Bogotá D.C. Colombia
Tel: 5714320160 Ext 4302
dcuellar@cancer.gov.co
Giancarlo Buitrago Gutiérrez

Médico. MSc en Epidemiología Clínica. PhD en Economía.
Departamento de Cirugía. Instituto de Investigaciones Clínicas. Facultad de Medicina.

Universidad Nacional de Colombia
Carrera 45 # 26-85 Bogotá D.C. Colombia
Tel: 5713165000 Ext 15107
gbuitragog@unal.edu.co
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treatment outcome
Running tittle: Risk Factors for Recurrence of Thyroid Cancer
Key words: thyroid neoplasms, neoplasm recurrence, therapy, iodine radioisotopes,

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ABSTRACT
Background: Patients with excellent response to initial therapy have a low rate of
tumor recurrence. The objective of this study was to evaluate the rate of early tumor
recurrence in patients with intermediate- risk papillary thyroid cancer who had an
excellent response to initial treatment and identify risk factors.
Methods: This retrospective cohort study included 217 patients with American
Thyroid Association (ATA) intermediate-risk papillary thyroid cancer who had a

documented excellent response to initial treatment (total thyroidectomy and adjuvant
therapy with 100 -150 mCi [3.7-5.5 GBq] of radioactive iodine [RAI]). The assessed
outcome was recurrence, defined as new evidence of disease after any disease-free
period. Multivariate logistic regression and Cox regression models were used to determine
the factors associated with recurrence upon recording clinical, surgical and pathology
variables.
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Results: Sixteen cases (7.4%) of recurrent disease were documented after a median
follow-up period of 42 months (range 17 to 88 months). Structural recurrence was
documented in 10 patients (62.5%) and biochemical in the remaining six patients. The
logistic regression model identified a significant association between early recurrence and
pN1b involvement (OR 10.81 [1.87-62.59]), lateral neck RAI uptake (OR 6.06 [1.67-22]),
and pre-ablation thyroglobulin >10 ng/ml (OR 4.01 [1.16-13.85]). Variables that proved
significant in the Cox regression model were: pN1b involvement (HR 9.6 [1.91-48.52]) and
lateral neck RAI uptake (HR 5.95 [1.86-18.97]).
Conclusion: The observed early recurrence rate of 7.4% is uncharacteristically high

for a population of patients who had an excellent response to initial treatment. The
significant association that was found between recurrent disease and lateral neck lymph-
node metastasis, lateral neck I131 uptake in post therapy whole-body scan, and pre-
ablation thyroglobulin levels >10 ng/ml indicate that early recurrence (<5 years) most likely
indicates progression of micrometastatic disease already present at diagnosis and
unsuccessfully eradicated with initial therapy.
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INTRODUCTION
The intermediate-risk category defined by the American Thyroid Association (ATA)

comprises a heterogeneous population of patients who have malignant tumors with

widely ranging stages (from T1N0 to T3N1B), different degrees of biological

aggressiveness, and various combinations of risk factors, including microscopic
extrathyroidal extension, radioactive iodine (RAI)-avid neck metastases in the first post-
therapy whole-body scan, aggressive histology (for example, tall cell, hobnail cell variant,
columnar cell variant), vascular invasion in papillary cancer patients, and clinical evidence
of neck lymph node involvement (1). No distant metastases are present at diagnosis, and
with appropriate surgical resection and adjuvant RAI therapy the long-term prognosis is
very good (2). Current treatment focuses on controlling persistent disease and preventing
recurrence (3). Persistent disease is quite frequent despite good overall survival.
The rate of long-term recurrence is reported to be less than 4% once an excellent response
to initial treatment is achieved (4-7), regardless of the initial risk estimate. Intermediate-
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risk patients are clinically characterized by having suspected albeit unrecognized residual
disease. Early recurrence (<5 years) most likely indicates progression of micrometastatic
disease already present at diagnosis and unsuccessfully eradicated with initial therapy (8).
It is not sufficient to simply classify patients as intermediate-risk and it is important

to separate patients with ‘lower risk features’ from those with ‘higher risk features’ in
order to personalize optimal treatment and monitoring. Traditional risk stratification
systems are not sufficiently reliable (1, 9) for at least two reasons: a) they are primarily
based on information from surgical pathology, inherently limited by the extent and
completeness of surgical resection (10), and the accuracy of specimen labeling; and b) the
effect of therapy is not integrated into risk assessment (4-7), including information
provided by post therapeutic RAI whole-body scanning about presence and staging of
residual disease and RAI avidity. In addition, there is paucity of data regarding treatment of
intermediate-risk patients. Therefore, the objective of this investigation was to identify risk
factors associated with early tumor recurrence in a cohort of patients with intermediate-
risk thyroid cancer with documented excellent response to initial treatment.
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MATERIALS AND METHODS
Upon obtaining approval from the institutional Research Board we retrospectively

reviewed physical and electronic medical records of all patients with differentiated thyroid
cancer (DTC) referred to the National Cancer Institute (Instituto Nacional de Cancerología
[INC]) in Bogotá, Colombia, between January 2009 and December 2013. We identified
patients older than 18 years of age with ATA 2009 intermediate-risk papillary thyroid
cancer (PTC) evident on surgical histopathology whose initial treatment included total
thyroidectomy and RAI therapy. Surgical procedures performed within one year of the first
surgery to optimize control of loco-regional disease were considered as part of the initial
treatment. To reduce heterogeneity only patients staged between T2N1 and T3N1 were
included. All patients had been treated with an administered RAI activity between 100 and
150 mCi (3.7-5.5 GBq) in accordance with the institution’s guidelines (11). Most patients
received RAI therapy after 2-4 weeks of levothyroxine withdrawal (TSH ≥ 25 UI/L) and 11%
received RAI therapy after preparation with recombinant human TSH (rhTSH), 0.9 mg i.m.
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on 2 consecutive days, followed by RAI on the third day and posttherapeutic scanning on
the fifth day. Patients were excluded if they had not received RAI therapy within 15
months of the first surgery, or if follow-up was less than 12 months after RAI therapy, or if
Tg levels were <1 ng/ml in the presence of TG-Ab persistently over >60 ng/ml, or if their
medical records had insufficient information to allow initial risk stratification and response
to initial treatment. We required at least 1 year of follow-up after treatment response
assessment, or until disease recurrence was documented, whichever occurred first. Only
patients with excellent response to initial treatment were recruited. To establish response
to initial treatment we examined all patient data obtained between 6 and 24 months after
initial RAI therapy, incorporating results from clinical exams, neck ultrasounds, FNA, RAI
whole-body scans, and measurements of stimulated and suppressed Tg using a
chemiluminescent assay (Immulite 2000 Thyroglobulin; Diagnostic Products, Los Angeles,
CA) with a functional sensitivity of 0.2 ng/ml. Starting in 2011, all Tg values were measured
using the ECLIA electrochemiluminescence assay (Roche Diagnostics International, SL) with
a functional sensitivity of 0.04 ng/ml. An excellent response required i) both suppressed
and stimulated thyroglobulin (Tg) levels <1 ng/ml; ii) antithyroglobulin antibodies (TgAb)
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<60 ng/ml (6); iii) neck ultrasound showing no evidence of disease, and; iv) negative cross-
sectional images or RAI whole-body scan (4). The primary outcome was recurrence defined
as new evidence of biochemical, structural or functional disease after any disease-free

period. Biochemical recurrence was defined as suppressed Tg levels ≥ 1 ng/ml or
stimulated Tg levels ≥ 2 ng/ml, or a progressive increase in TgAb in consecutive follow-up

exams. Structural recurrence required evidence of disease confirmed by cytology or
histology, or conclusive findings from ultrasound, cross-sectional images, RAI whole-body
scans or FDG PET/CT (4). Other data obtained from medical records included: age, sex,
TNM staging, extrathyroidal extension, multifocality, vascular invasion, histological
changes, thyroid capsule invasion, positive ink margins, lymph node involvement,
extranodal extension, surgical extent, reoperative surgery, extent of lymphadenectomy,
RAI administered activity, posttherapeutic whole-body scan results, and TSH, Tg, and TgAb
levels.
Statistical analysis
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A multivariate logistic regression model was used to identify the factors associated
with the risk of recurrence. In addition, recurrence-free survival was estimated using the
Kaplan-Meier method. The log-rank test was used to compare bivariate survival functions.
Cox proportional hazard regressions were used to assess the risk associated with
recurrence. Hazard ratio (HR) and 95% confidence interval (CI) were calculated in the
model and the proportionality assumption was evaluated by the Schoenfeld residual
analysis. The multivariate models included variables that were significant in the bivariate
analysis and those that were clinically relevant according to the literature and/or expert
opinions. The analyses were performed using Stata 11.2®.
RESULTS
Patients: We identified 441 patients with intermediate-risk papillary thyroid cancer

and extent of disease between T2N1 and T3N1. A total of 52 cases (11.7%) were excluded
because they were lost to follow-up before response to therapy was determined. Of the
389 remaining patients, an excellent response was documented in 217 (56%), which
constituted the study cohort. Patient and tumor characteristics are described in Table 1.
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Most of the patients were females (93.1%). The average age was 51±11.8 years and the
most common tumor features were size ≤2 cm (68.2%), microscopic extrathyroidal
extension (90.8%), and involvement of the central lymph nodes (59%). Few cases of
aggressive histological variants (6%) or vascular invasion (1.9%) were documented. All of
the patients were treated with total thyroidectomy (86.2% with prophylactic central neck
dissection) and RAI therapy (100-150 mCi). Overall, 118 patients (54.4%) had an initial
surgery performed in a non-specialized institution before referral to our center. Most of
these surgeries were total thyroidectomies performed by competent surgeons. Twenty

such patients plus one of our own required a reoperation, either because of an initially
partial surgery (2 lobectomies and 11 hemithyroidectomies) or a postoperative diagnosis
of residual disease in lateral neck lymph nodes (n = 8) after total thyroidectomy (including
a patient initially operated in our center).
Outcomes: The median follow-up time for the whole cohort was 42 months (range
17 to 88 months, interquartile range [IR] of 35 months). Disease recurrence was
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documented in 16 cases (7.4%), as shown in Table 2. The recurrence was structural in 10

cases (62.5%), 9 of them in cervical lymph nodes outside the initial surgical field and the
last one in the soft tissues of the thyroid bed. Nodal recurrences were treated with
lymphadenectomy in 8 patients (followed by RAI therapy in 5 patients). One patient died
before surgery due to an unrelated cardiac event. Soft tissue local recurrence was treated
with RAI therapy. At the last follow-up, 5 patients with structural recurrence had been
rendered disease-free (including the patient with local recurrence) whereas 4 had
persistent disease (3 structural and 1 biochemical persistence). Six patients (37.5%) were
diagnosed with a biochemical recurrence. One of them was treated with empiric RAI
therapy but 40 months later displayed FDG-avid structural progression in neck lymph
nodes. Two additional patients further progressed to structural recurrence (in thyroid bed
and lungs, respectively). Both received a second dose of RAI. At the time of final follow-up
they were still under surveillance awaiting evaluation in terms of response to treatment.
Of the 3 remaining patients, 2 displayed persistently detectable thyroglobulin levels
(suppressed/stimulated Tg levels: 0.04/1.95 ng/ml and 2.11/25.4 ng/ml, respectively) with
no evidence of structural disease and the other was lost to follow-up.
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Multivariate Logistic Regression Model: Multivariate analysis included variables
that displayed a p value <0.20 in bivariate analyses, i.e., tumor size (p=0.059), TNM lymph
node staging (p=0.011), pre-ablation stimulated Tg value (p=0.032), and lateral neck RAI
uptake in post therapy whole-body scans (p=0.007). Backward elimination and stepwise
regression was applied with an input probability of p <0.05. Prognostic factors for
recurrence (p <0.05) were: pN1b involvement, pre-ablation Tg >10 ng/ml, and lateral neck
RAI uptake (Table 3).
Cox Regression Model: Cox analysis included variables that displayed a p value
<0.20 in bivariate analyses, i.e., tumor size (p = 0.128), TNM lymph node staging (p =
0.001), use of human recombinant thyrotropin (rhTSH, Genzyme) (p = 0.062), pre-ablation
stimulated Tg value (p = 0.062), and lateral neck RAI uptake in post-treatment whole-body
scans (p = 0.003). Prognostic factors of recurrence were: pN1b involvement and lateral
neck RAI uptake (Table 4) (Figure 1). The Chi-square test used to test for non-
proportionality of hazards in the Cox model showed non-violation of the assumption (p =
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0.6685). Schoenfeld residual plots were made for each variable included in the model.
There was no violation of the proportionality hypothesis (p = 0.6322 for N1b and p =
0.9168 for lateral neck RAI uptake).
Recurrence-Free Survival: Kaplan Meier recurrence-free survival could not be

estimated for 50% of the cohort due to the infrequent occurrence of the event: The
incidence density was 1.97 events per 100 person-years (CI 95% 1.20-3.21). Recurrence-
free survival at 3 years was 94.7% (range, 18 to 80 months; median, 36 months). Patients
who were recurrence-free as of December 2016 and those who were lost to follow-up
were censored, since their status could not be established.
DISCUSSION
In a strictly clinical sense, a true recurrence is defined as biochemical or structural

identification of disease in a patient previously thought to have no clinical evidence of
disease (NED) following treatment (12). Nevertheless, according to our results, some
patients with no evidence of disease may in fact harbor unrecognized microscopic
persistent disease that may go undetected at the time of response to treatment
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assessment only to be diagnosed months later upon progressing to a macroscopic scale or
after reaching the threshold of clinical detection (8,13). Patients with differentiated
thyroid cancer (DTC) that achieve clinical remission after initial treatment have a low risk
of long-term recurrence regardless of their initial risk stratification (4-7). In the series by
Tuttle et al., the few recurrences that occurred after an excellent response to initial
therapy were diagnosed between 4 to 11 years after initial treatment (4). In our study, the
rate of recurrent disease after a period of NED was 7.4%, which is higher than expected for
a relatively short median follow-up of 42 months raising the question about the existence
of occult (i.e., persistent) disease since the onset (8,13). Incomplete tumor resection is a
prognostic factor associated with high risk of recurrence (1). In fact, early reoperations,
within months of the initial thyroidectomy most likely reflect persistent rather than
recurrent disease (13). Twenty-one patients required reoperations either for completion
thyroidectomy or dissection of previously unrecognized involved lymph nodes. Recurrent
disease was eventually documented in 3 (14%) of these patients. Reoperations are
technically demanding because of the need to dissect on scarred and fibrotic tissue where
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anatomical planes have been altered by the initial surgery. They have a higher risk of
complications (12) and have been independently associated with all-cause and disease-
specific mortality (13). Nonetheless, this variable did not reach significance in our
multivariate analyses, maybe because of the small sample size.
Establishing an excellent response is not always straightforward, especially in

retrospective studies, where not all biochemical examinations are performed in the same
center and may not be comparable. Thyroglobulin antibodies can affect Tg measurements
(14), whereas ultrasound findings are not always specific and results from fine needle
aspirations (FNA) are not always conclusive. Even after obtaining negative biochemical and
imaging results at predetermined time points (usually first 24 months after initial therapy),
there is still a chance that persistent disease may go undetected.
Two very closely related variables, tumor involvement of the lateral neck lymph
nodes and lateral neck RAI uptake in post-treatment scans, were significantly prevalent in
the multivariate analysis, in both the logistic and the Cox regressions. In addition, the
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multivariate logistic regression model established a statistically significant association
between tumor recurrence and pre-ablation stimulated Tg >10 ng/ml (Tables 2 and 3).
Meer et. al. reported that lateral neck lymph node involvement is a prognostic
factor for recurrent disease (15). Other authors found that, not only the localization but
also the number and size of positive lymph nodes, the presence of extranodal extension,
and the size of the tumor focus are prognostic factors that influence the risk of recurrence
(16, 17). These factors have recently been incorporated into the 2015 ATA guidelines (18)
but they could not be assessed in our study.
Lateral neck RAI uptake in post-treatment scans is almost invariably associated with
residual tumor in neck lymph nodes or soft tissue. Nevertheless, the effectiveness of RAI
therapy in this scenario is unreliable and less effective for macroscopic residual lymph
node metastases (19,20). The recent introduction of hybrid SPECT/CT images has helped to
clarify the role of RAI therapy to treat lymph node metastases (21,22). Schmidt et al. (21)
addressed the relationship between the size of involved lymph nodes and the success rate
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of RAI therapy. They found that 94% of RAI-avid nodal metastatic deposits smaller than 0.9
mL were successfully eliminated by radioiodine.
Pre-ablation unstimulated Tg (i.e., quantitated approximately 30 days after surgery)

has been found to be an important predictor of recurrence for patients with DTC (23-29).
Park et. al. reported that patients with a pre-ablation Tg ≥ 10 ng/ml were 25.5 times more
likely to experience therapeutic failure than those with a Tg <10 ng/ml (95% CI = 5.43–
119.60; p < 0.001) (23). In a recent meta-analysis, Webb et al. (24) found a positive
predictive value (PPV or probability of having persistent disease) of only 47% for a pre-
ablation Tg >10 ng/ml (24). This seemingly low PPV can be explained by the fact that
normal remnant thyroid tissue, present in nearly all patients, continues to synthesize and
release Tg after thyroidectomy. On the contrary, patients with postoperative pre-ablation
Tg values <10 ng/ml only had a 6% likelihood of having persistent disease (24). In fact, 85%
of our patients had a pre-ablation Tg <10 ng/ml.
Limitations of our study include its retrospective nature and a short duration of
follow-up. A median follow-up of 42 months may be too short because most true
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recurrences are expected to occur after the first 5 years in patients with an excellent
response. An effort was made to control information bias through a meticulous data
collection process conducted by only one researcher. By following a pre-established

treatment protocol (11), it was possible to obtain uniform records of patient staging,
treatment, and follow-up. Only patients who had an excellent response to initial treatment
were included in order to compensate for differences in diagnostic, therapeutic, and TNM
staging procedures, a common situation during the first 2 years, especially if not all
procedures are performed in the same institution. Nevertheless, we may have

inadvertently enrolled patients with a higher risk of recurrence; this could partially explain
the high recurrence rate in our study. The 2015 ATA Guidelines (18) state that patients
with at least one involved lymph node >3 cm should be stratified as high-risk. Our cohort
includes patients treated between January 2009 and December 2013, so risk stratification
and management decisions were made according to the 2009 ATA Guidelines (1). Some of
the newer recommendations, such as the size of metastatic deposits, did not consistently
appeared in histopathology reports before 2016. Therefore some N1 patients with nodal
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macrometastases (≥ 3 cm) might have been downstratified and some N1 patients with ≤5
micrometastases (<0.2 cm) might have been upstratified as intermediate risk. To reduce
heterogeneity, we purposely did not include the entire spectrum of intermediate-risk
patients, only those with greater extent of disease (between T2N1 and T3N1b). Patients
with TgAb levels <60 ng/ml were included in the response to treatment analysis (6) and
this might have induced some falsely undetectable serum Tg levels (14). Loss of some
patients during follow-up could not be controlled because they were referred to other
institutions by their health insurance companies. Possible confounding biases were
controlled for by the multivariate logistic regression and Cox regression analyses, in
accordance with the available literature. The final proposed models were adjusted to the
data that were obtained, as seen in the analyses of the diagnostics and validations
performed for each model. Since the final sample size was smaller than expected, a type II
error may have occurred, as shown by the amplitude of the models’ confidence intervals.
Consequently, variables such as pre-ablation stimulated Tg >10 ng/ml, that did not reach
statistical significance in the Cox regression model, might have proved significant in a
larger sample size. Some of intermediate-risk variables, such as aggressive histological
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variants, vascular invasion, and extranodal extension, could not be analyzed due to their
infrequent occurrence.
In conclusion, the observed early recurrence rate of 7.4% is uncharacteristically

high for a population of patients who had an excellent response to initial treatment. The
significant association found between recurrent disease and lateral neck lymph-node
metastasis, lateral neck RAI uptake in post therapy whole-body scan, and pre-ablation Tg
levels >10 ng/ml may indicate that the so called ”early” recurrences may, in fact, be due to
unrecognized occult residual, regional or micrometastatic disease that enlarges to reach

the threshold of clinical detection (12,13).
ACKNOWLEDGMENTS
We thank Dr. Alfredo Romero and Dr. Felipe Fierro for their collaboration in the
definition of specific variables and other important concepts.
DISCLOSURE
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No competing financial interests exist.
FUNDING
This study was funded with resources provided by the Instituto Nacional de
Cancerología.
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REFERENCES
1. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, Mclever
B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM 2009 Revised American
Thyroid Association Management Guidelines for patients with thyroid nodules and
differentiated thyroid cancer. Thyroid 19(11):1-48.
2. Ruel E, Thomas S, Dinan M, Perkins JM, Roman SA, Sosa JA 2015 Adjuvant radioactive
iodine therapy is associated with improved survival for patients with intermediate-risk
papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-36.

3. Lamartina L, Durante C, Filetti S, Cooper DS 2015 Low-risk differentiated thyroid cancer
and radioiodine remnant ablation: A systematic review of the literature. J Clin Endocrinol
Metab 100(5):1748-61.
4. Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin
JA, Shaha A 2010 Estimating risk of recurrence in differentiated thyroid cancer after total
thyroidectomy and radioactive iodine ablation: Using response to therapy variables to
Thyroid
modify the initial risk estimates predicted by the new American Thyroid Association
Staging System. Thyroid 20(12):1341-9.
5. Castagna MG, Maino F, Cipri C, Belardini V, Theodoropoulou A, Cevenini G, Pacini F 2011
Delayed risk stratification, to include the response to initial treatment (surgery and
radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer
patients. Eur J Endocrinol 165(3):441-6.
6. Jeon MJ, Kim WG, Park WR, Han JM, Kim TY, Song DE, Chung KW, Ryu JS, Hong SJ, Shong
YK, Kim WB 2013 Modified risk stratification for predicting recurrence using the response
to initial therapy in patients with differentiated thyroid carcinoma. Eur J Endocrinol
170(1):23-30.
7. Vaisman F, Momesso D, Bulzico DA, Pessoa CH, Dias F, Corbo R, Vaisman M, Tuttle RM
2012 Spontaneous remission in thyroid cancer patients after biochemical incomplete
response to initial therapy. Clin Endocrinol (Oxf) 77(1):132-8.
8. Ringel MD 2011 Metastatic dormancy and progression in thyroid cancer: Targeting cells
in the metastatic frontier. Thyroid 21(5):487-92.
Page 14 of 24
14
9. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W, European Thyroid
Cancer Taskforce 2006 European consensus for the management of patients with
differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154(6):787-

803.
10. Clerc J, Verburg FA, Avram AM, Giovanella L, Hindié E, Taïeb D 2017 Radioiodine
treatment after surgery for differentiated thyroid cancer: a reasonable option. Eur J Nucl
Med Mol Imaging 44(6):918-25.
11. Garavito G, Llamas-Olier A, Cadena E, De los Reyes A, Hurtado G, Rojas L, Romero-Rojas

A, Martínez MC, De Francisco J, Mejía MC 2010 Manejo multidisciplinario del cáncer
diferenciado de tiroides en el Instituto Nacional de Cancerología. Rev Colomb Cancerol
14(2):65-77.
12. Tufano RP, Clayman G, Heller KS, Inabnet WB, Kebebew E, Shaha A, Steward DL, Tuttle
RM, American Thyroid Association Surgical Affairs Committee Writing Task Force 2015
Management of recurrent/persistent nodal disease in patients with differentiated thyroid
cancer: A critical review of the risks and benefits of surgical intervention versus active
Thyroid
surveillance. Thyroid 25(1):15-27.

13. Young S, Harari A, Smooke-Praw S, Ituarte PH, Yeh MW 2013 Effect of reoperation on
outcomes in papillary thyroid cancer. Surgery 154(6):1354-62.
14. Spencer C, Fatemi S 2013 Thyroglobulin antibody (TgAb) methods – Strengths, pitfalls
and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer.
Best Pract Res Clin Endocrinol Metab 27(5):701-12.
15. de Meer SG, Dauwan M, de Keizer B, Valk GD, Borel Rinkes IH, Vriens MR 2012 Not the
number but the location of lymph nodes matters for recurrence rate and disease-free
survival in patients with differentiated thyroid cancer. World J Surg Jun;36(6):1262–7.
16. Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, Tufano RP, Tuttle
RM, American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid
Cancer Nodal Surgery 2012 The prognostic significance of nodal metastases from papillary
thyroid carcinoma can be stratified based on the size and number of metastatic lymph
nodes, as well as the presence of extranodal extension. Thyroid 22(11):1144-52.
17. Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, Travagli JP,
Schlumberger M 2005 Prognostic factors for persistent or recurrent disease of papillary
Page 15 of 24
15
thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the
thyroid capsule at initial diagnosis. J Clin Endocrinol Metab 90(10):5723–9.
18. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F,
Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL,
Tuttle RM, Wartofsky L 2016 2015 American Thyroid Association management guidelines for
adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 26(1):1-133.
19. Creach KM, Gillanders WE, Siegel BA, Haughey BH, Moley JF, Grigsby PW 2010
Management of cervical nodal metastasis detected on I131 scintigraphy after initial

surgery of well-differentiated thyroid carcinoma. Surgery 148(6):1198-204.
20. Verburg FA, de Keizer B, Lam MG, de Klerk JM, Lips CJ, Borel-Rinkes IH, van Isselt JW
2007 Persistent disease in patients with papillary thyroid carcinoma and lymph node
metastases after surgery and iodine-131 ablation. World J Surg 31(12):2309-14.
21. Schmidt D, Linke R, Uder M, Kuwert T. 2010 Five months’ follow-up of patients with
and without iodine-positive lymph node metastases of thyroid carcinoma as disclosed by
131
I-SPECT/CT at the first radioablation. Eur J Nucl Med Mol Imaging 37(4):699-705.
Thyroid
22. Avram AM 2012 Radioiodine scintigraphy with SPECT/CT: An important diagnostic tool
for thyroid cancer staging and risk stratification. J Nucl Med 53(5):754-64.
23. Park HJ, Jeong GC, Kwon SY, Min JJ, Bom HS, Park KS, Cho SG, Kang SR, Kim J, Song HC,
Chong A, Yoo SW 2014 Stimulated serum thyroglobulin level at the time of first dose of
radioactive iodine therapy is the most predictive factor for therapeutic failure in patients
with papillary thyroid carcinoma. Nucl Med Mol Imaging 48(4):255-61.
24. Webb RC, Howard RS, Stojadinovic A, Gaitonde DY, Wallace MK, Ahmed J, Burch HB
2012 The utility of serum thyroglobulin measurement at the time of remnant ablation for
predicting disease-free status in patients with differentiated thyroid cancer: a meta-
analysis involving 3947 patients. J Clin Endocrinol Metab 97(8):2754–63.
25. Lee JI, Chung YJ, Cho BY, Chong S, Seok JW, Park SJ 2013 Postoperative-stimulated
serum thyroglobulin measured at the time of 131I ablation is useful for the prediction of
disease status in patients with differentiated thyroid carcinoma. Surgery 153(6):828–35.
26. Rosario PW, Furtado MdS, Mourâo GF, Calsolari MR 2015 Patients with papillary
thyroid carcinoma at intermediate risk of recurrence according to American Thyroid
Page 16 of 24
16
Association Criteria can be reclassified as low risk when the postoperative thyroglobulin is
low. Thyroid 25(11):1243-8.
27. Nascimento C, Borget I, Ghuzlan AA, Deandreis D, Chami L, Travagli JP, Hartl D,
Lumbroso J, Chougnet C, Lacroix L, Baudin E, Schlumberger M, Lebulleux S 2011 Persistent
disease and recurrence in differentiated thyroid cancer patients with undetectable

postoperative stimulated thyroglobulin level. Endocr Relat Cancer 18(2):R29-R40.
28. Ibrahimpasic T, Nixon IJ, Palmer FL, Whitcher MM, Tuttle RM, Shaha A, Patel SG, Shah
JP, Ganly I 2012 Undetectable thyroglobulin after total thyroidectomy in patients with low-
and intermediate-risk papillary thyroid cancer - Is there a need for radioactive iodine
therapy? Surgery 152(6):1096-1105.
29. Kim MH, Ko SH, Bae JS, Lim DJ, Baek KH, Lee JM, Kang MI, Cha BY 2012 Combination of
initial stimulation thyroglobulins and staging system by revised ATA guidelines can
elaborately discriminate prognosis of patients with differentiated thyroid carcinoma after
high-dose remnant ablation. Clin Nucl Med 37(11):1069-74.
Thyroid
Thyroid
Page 17 of 24
Sex
Classic
Female
> 40 mm
≤ 20 mm
Tumor size
Multifocality
21 to 40 mm
Age ≥ 55 years
Characteristics
Vascular invasion
Positive ink margins
Histological variants
Extrathyroidal extension
Thyroid capsule involvement

Table 1. Patient characteristics
n (%)
4 (1.8)
9 (4.1)
89 (41.0)
52 (24.0)
60 (27,6)
60 (27.7)
97 (44.7)
197 (90.8)
196 (90.3)
148 (68.2)
202 (93.1)
Total=217
17
Thyroid
T3
T2
Nx
N0
N1a
N1b
Solid
Tall cell
Follicular
Clear cell
Oncocytic
Ipsilateral
Contralateral
No information
pT classification
pN classification
Diffuse sclerosing
Lateral lymph node involvement

Central lymph node involvement
1 (0.5)
1 (0.5)
2 (0.9)
2 (0.9)
9 (4.1)
4 (1.8)
16 (7.4)
17 (7.8)
30 (14.3)
22 (10.1)
29 (13.4)
95 (43.8)
71 (32.7)
26 (12.0)
201 (92.6)
118 (54.4)
150 (69.1)
18
Page 18 of 24
Thyroid
Page 19 of 24
150 mCi
100 mCi
< 10 ng/mL
≥ 10 ng/mL
Average (SD)
Average (SD)
No information
I131 activity (mCi)

rhTSH-Stimulated TSH
SD, standard deviation

Pre-ablation stimulated Tg
Reoperation before ablation
Initial surgery to ablation delay (months)

Initial diagnosis to surgery delay (months)
3 (1.4)
21 (9.7)
6.3 (3.1)
5.4 (3.9)
24 (11.1)
37 (17.1)
29 (13.3)
180 (82,9)
185 (85.3)
19
Page 20 of 24
20
Table 2. Characteristics of patients with recurrence
Age Sex Size Salvage *Final

pTNM Recurrence Tg(off)

(years) (mm) intervention status
1 57 M 30 T3 N1a Structural 60.5 Surgery NED
2 51 F 25 T3 N1a Structural 6.36 Surgery SED

3 53 F 24 T3 N1a Structural 5.48 Surgery NED
4 40 F 28 T3 N1a Structural 3.24 Surgery and NED

RAI
5 60 F 30 T3 Nx Structural 0.26 Surgery and NED

RAI
6 53 F 30 T3 N0 Structural 0.97 Surgery and SED

Thyroid
RAI
7 54 F 17 T3 Nx Structural 41.2 Surgery and SED

RAI
8 38 F 14 T3 N1b Structural 66.8 Surgery and BED

RAI
9 57 F 10 T3 N1a Structural 19.3 RAI NED
10 63 F 8 T3 N0 Structural 1.96 - D
11 62 F 10 T3 N1b Biochemical 0.90 RAI SED
12 62 F 19 T3 N1b Biochemical 13.4 NONE SED
13 65 M 22 T3 Nx Biochemical 1.08 NONE SED

Thyroid
Page 21 of 24
16
15
14
32
35
35
F
F
F
50
10
25
death from unrelated causes.

T3 N1b
T3 N1b
T3 N1b
Biochemical
Biochemical
Biochemical
* Final status at last follow up checkpoint (December 2016).

0.69
1.68
0.65
NONE
NONE
NONE
BED
BED
Lost to
follow up
Tg (off), pre-ablation TSH-stimulated thyroglobulin value (ng/ml); NED, no evidence of

disease; BED, biochemical evidence of disease; SED, structural evidence of disease; D,
21
Thyroid
Nx
N0
N1a
N1b
10 ng/ml
Covariables
post-treatment scan
TNM for lymph nodes
Pre-ablation stimulated Tg >
Lateral neck uptake of RAI in

OR
5.49
6.06
4.01
2.27
10.81
Table 3. Logistic Regression Model for Recurrence
(CI 95%)
(0.80-37.57)
(1.87-62.59)
(1.67-22.00)
(1.16-13.85)
(0.40-12.83)
p
0,083
0,008
0,006
0,028
0,355
22
Page 22 of 24
Thyroid
Page 23 of 24
Nx
N0
N1a
N1b
ng/mL
Covariables
treatment scan
HR
5.72
Lateral neck RAI uptake in post- 5.95

Pre-ablation stimulated Tg > 10 3.10
9.63
2.27
(CI 95%)
(0.98-9.80)
(1.86-18.97)
(0.95-34.61)
(1.91-48.52)
(0.43-12.07)
Table 4. Cox Regression Model for Recurrence-Free Survival
0,054
0,003
0,058
0,006
0,333
23
Thyroid
in post-therapy whole-body scans.

Figure 1. Survival curves based on TNM lymph node staging and lateral neck uptake of I131
24
Page 24 of 24

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Thyroid

Augusto Enrique Llamas Olier

Médico. Especialista en Medicina Nuclear

Grupo de Medicina Nuclear. Instituto Nacional de Cancerología.

Calle 1 # 9-85 Bogotá D.C. Colombia

Diana Isabel Cuéllar Rivera

Bacterióloga. MSc en Epidemiología

Grupo de Investigación Epidemiológica del Cáncer. Instituto Nacional de Cancerología.

Calle 1 # 9-85 Bogotá D.C. Colombia

Tel: 5714320160 Ext 4302

Giancarlo Buitrago Gutiérrez

Departamento de Cirugía. Instituto de Investigaciones Clínicas. Facultad de Medicina.

Tel: 5713165000 Ext 15107

Key words: thyroid neoplasms, neoplasm recurrence, therapy, iodine radioisotopes,

Thyroid Association (ATA) intermediate-risk papillary thyroid cancer who had a

Conclusion: The observed early recurrence rate of 7.4% is uncharacteristically high

The intermediate-risk category defined by the American Thyroid Association (ATA)

comprises a heterogeneous population of patients who have malignant tumors with

widely ranging stages (from T1N0 to T3N1B), different degrees of biological

It is not sufficient to simply classify patients as intermediate-risk and it is important

Upon obtaining approval from the institutional Research Board we retrospectively

as new evidence of biochemical, structural or functional disease after any disease-free

stimulated Tg levels ≥ 2 ng/ml, or a progressive increase in TgAb in consecutive follow-up

Patients: We identified 441 patients with intermediate-risk papillary thyroid cancer

these surgeries were total thyroidectomies performed by competent surgeons. Twenty

documented in 16 cases (7.4%), as shown in Table 2. The recurrence was structural in 10

Recurrence-Free Survival: Kaplan Meier recurrence-free survival could not be

In a strictly clinical sense, a true recurrence is defined as biochemical or structural

Establishing an excellent response is not always straightforward, especially in

but they could not be assessed in our study.

Pre-ablation unstimulated Tg (i.e., quantitated approximately 30 days after surgery)

collection process conducted by only one researcher. By following a pre-established

procedures are performed in the same institution. Nevertheless, we may have

In conclusion, the observed early recurrence rate of 7.4% is uncharacteristically

unrecognized occult residual, regional or micrometastatic disease that enlarges to reach

No competing financial interests exist.

papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-36.

differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154(6):787-

11. Garavito G, Llamas-Olier A, Cadena E, De los Reyes A, Hurtado G, Rojas L, Romero-Rojas

surveillance. Thyroid 25(1):15-27.

Management of cervical nodal metastasis detected on I131 scintigraphy after initial

disease and recurrence in differentiated thyroid cancer patients with undetectable

Thyroid capsule involvement

Lateral lymph node involvement

I131 activity (mCi)

SD, standard deviation

Initial surgery to ablation delay (months)

Age Sex Size Salvage *Final

pTNM Recurrence Tg(off)

1 57 M 30 T3 N1a Structural 60.5 Surgery NED

2 51 F 25 T3 N1a Structural 6.36 Surgery SED

3 53 F 24 T3 N1a Structural 5.48 Surgery NED

4 40 F 28 T3 N1a Structural 3.24 Surgery and NED

5 60 F 30 T3 Nx Structural 0.26 Surgery and NED

6 53 F 30 T3 N0 Structural 0.97 Surgery and SED

7 54 F 17 T3 Nx Structural 41.2 Surgery and SED

8 38 F 14 T3 N1b Structural 66.8 Surgery and BED

9 57 F 10 T3 N1a Structural 19.3 RAI NED

11 62 F 10 T3 N1b Biochemical 0.90 RAI SED

12 62 F 19 T3 N1b Biochemical 13.4 NONE SED

13 65 M 22 T3 Nx Biochemical 1.08 NONE SED

death from unrelated causes.