Keywords TENIS - negative Thyroglobulin antibody - differentiated thyroid carcinoma - outcome
- progression-free survival.
Introduction
During the management of differentiated thyroid carcinoma (DTC), it is not uncommon
to come across cases with detectable or elevated thyroglobulin (Tg) and a negative
diagnostic whole-body iodine-131 scan (DxWBS I). This is referred to as Tg elevation
and negative iodine scintigraphy (TENIS) syndrome and is seen in 10%–27%.[[1 ]],[[2 ]] This causes considerable diagnostic and therapeutic dilemma. In such patients,
ultrasound (US) neck helps in identifying local disease which can be managed appropriately
and may sometimes even eliminate the need for empiric radioactive iodine therapy (eRAI).
However, when the neck US is negative, these patients might need further studies such
as computed tomography (CT) of the chest, and fluorodeoxyglucose positron emission
tomography/CT (FDG PET/CT) to localize iodine nonavid disease and to decide on further
treatment plans. These expensive imaging modalities may not be affordable to many.
Many such patients may undergo eRAI with high dose I131. The posttherapy scan (RxWBS
I) after eRAI may show iodine avid disease or may be negative. The use of eRAI is
controversial and all experts do not share the same view.[[3 ]],[[4 ]],[[5 ]],[[6 ]] Moreover, this may add to the cost of treatment and may not be a feasible option
in a resource-poor setting like ours. Hence, the management of TENIS patients, especially
those with negative US neck, poses a challenge. We aimed at evaluating this group
of TENIS patients (henceforth referred to as the TENIS subgroup) to see if factors
contributing to the outcome could be predicted. The objective of the present study
was to evaluate the prevalence of this TENIS subgroup in our population of DTC, their
clinicopathological, treatment characteristics, and outcome.
Subjects and Methods
This was a retrospective study conducted for which the institutional ethical committee
approval (dated November 9, 2020; IEC-AIMS-2020-ENDO-188) was given. The patients
were taken from the thyroid carcinoma database after taking their informed consent
for data collection and its usage for research purposes. Consecutive patients were
selected who fulfilled the following inclusion criteria and formed the study cohort
(TENIS subgroup).
Patients with DTC who at first or any subsequent evaluation had
A negative DxWBS I but had detectable stimulated Tg >1.0 ng/mL (when thyroid-stimulating
hormone (TSH) after thyroxine withdrawal was >30 micro IU/mL) on the day of the scan,
after having been on a low iodine diet for 3 weeksNegative Tg antibody (TgAb) defined
as any value below the upper limit of the reference range of the assay used and
Negative neck US.
Excluded were patients <18 years of age, those who had not received RAI ablation after
total thyroidectomy, other thyroid cancers, and those with insufficient data for analysis.
Out of this group, those who had at least three stimulated Tg on follow-up formed
the study cohort.
The approach to the treatment of DTC at our Institute was published elsewhere.[[7 ]] Risk stratification for recurrence/persistence was performed using the American
Thyroid Association (ATA) 2009 Guidelines.[[8 ]] The management of TENIS patients was based on histopathology reports, RxWBS I after
ablation, patient preference, and affordability after discussion at the Thyroid Tumor
Board, which comprised of all concerned specialists. The decision was made either
for follow-up at regular intervals or for further imaging such as chest CT or FDG
PET/CT to look for iodine nonavid lesions. If nonavid lesions were found, they were
treated appropriately. If FDG PET/CT was negative, either an eRAI was given or the
patients were kept under follow-up. If response to eRAI therapy was documented, additional
doses were given till the uptake disappeared in the RxWBS I after therapy and/or Tg
became undetectable. Further doses were withheld if the first eRAI treatment appeared
ineffective.
Short-term response to eRAI therapy was defined as the change in Tg from before eRAI
therapy to that of 6–12 months after treatment and the immediate RxWBS I findings
as follows:
Negative response: When RxWBS after eRAI was negative and Tg 6 to 12 months later,
did not fall or rose
Positive response: RxWBS after eRAI was positive or Tg dropped more than 50% in 6
to 12 months in those where RxWBS was negative
Partial response: RxWBS negative after eRAI and Tg drop 6 to 12 months later was <50%.
To evaluate the outcome at the last follow-up, clinical endpoints were used to define
five categories as recommended by Tuttle et al .[[9 ]]
No evidence of disease (NED), persistent biochemical disease (PBD), persistent structural
disease (PSD), recurrent disease (RD), and indeterminate disease (ID).
These were then grouped into two for the sake of analysis: favorable response (NED
and ID) and unfavorable response (PSD, PBD, and RD).
Laboratory assays
Tg level was determined by the Electrochemiluminescence Assay (ELECSYS 2010; Roche,
Switzerland). TgAb was measured using the ARCHITECT anti-Tg assay (Abbott, USA) from
2010 to mid 2017. From July 2017, ELECSYS anti-Tg assay (Roche Laboratories) was used.
TSH was assayed using the ARCHITECT TSH assay from 2010 to mid 2017. From then on,
the testing used the Electrochemiluminescence Assay (Roche). The reference range was
0.005–100 μIU/mL with a functional sensitivity of 0.014 μIU/mL.
Statistical analysis
Statistical analysis was performed using IBM SPSS version 20.0 software (IBM Corporation,
Armonk, NY, USA). Categorical variables were expressed as frequency and percentage.
Numerical variables were presented as median as well as mean and standard deviation.
Chi-square test was used for the comparison of quantitative data between the two groups.
Logistics analysis was used for univariate and multivariate analysis. Kaplan–Meier
method was used to calculate progression-free survival (PFS) and a log-rank test was
applied for calculating significance. Receiver operating characteristic (ROC) curve
analysis was used to mark the Tg cutoff values above which, both the sensitivity and
specificity for the unfavorable outcome reached an optimal value. The values of P < 0.05 were considered statistically significant with 95% of confidence interval.
Results
From a DTC database of 722 patients, 193 (26.7%) with TENIS were identified. Among
these, 101 patients had negative neck US and negative Tg antibody. From these, 64
patients with at least 3 subsequent Tg values and 2-year follow-up were included in
the present study (TENIS subgroup). Baseline characteristics of the study cohort are
described in [[Table 1 ]].
Table 1 Baseline characteristics of thyroglobulin elevation and negative iodine scintigraphy
subgroup (n=64)
More than 80% of the patients became TENIS by 1 year and almost half had Tg level
<10 at that time. Majority of the tumor types (84.4%) were papillary thyroid carcinoma
(PTC) and its variants and 43.8% belonged to the intermediate risk for recurrence
(ATA 2009). The mean duration of follow-up was 7.8 ± 2.5 years and 75% had 5–10 years
follow-up [[Table 2 ]].
Table 2 Follow-up and treatment modalities of thyroglobulin elevation and negative iodine
scintigraphy subgroup (n=64)
Since half the cohort had Tg level below 10 ng/mL, these patients were divided into
two groups, Tg <10 and Tg >10 for comparison [[Figure 1 ]]. The distribution of variables in the two Tg categories showed that basic variables
were comparable except that the low-risk ATA category was more common in Tg <10 group.
Figure 1 Comparison of the distribution of variables among Tg TENIS groups. Tg: Thyroglobulin,
TENIS: Thyroglobulin elevation and negative iodine scintigraphy
Follow-up
During follow-up, spontaneous drop in Tg level was seen in 27/64 patients (42.2%).
In the rest, distant metastases (DM) were detected in nine patients and lymph node
(LN) metastases appeared in 20 patients [[Table 2 ]]. LN metastases were detected by US in 12 patients, FDG-PET/CT in five patients,
posttherapy scan in one patient, and by both US and FDG-PET/CT in two patients. Further
evaluation including FDG-PET/CT scan was done for 18 subjects with high or increasing
Tg levels, out of which 14 were positive: LN metastasis in 7 and DM in 10 [[Table 3 ]]. Treatment constituted of LN dissection (LND-10), eRAI therapy (16), and external
beam radiation therapy (EBRT-7).
Table 3 Details of thyroglobulin elevation and negative iodine scintigraphy patients with
positive fluorodeoxyglucose-positron emission tomography/computed tomography scan
(n=14)
Empiric radioactive iodine therapy
In the TENIS subgroup of 64 patients, 16 (11 females and 5 males) were given eRAI
therapy [[Table 4 ]]. Tg at the time of TENIS ranged from 1.2 to 996 ng/mL. Among these, 12 had FDG
PET/CT Scan before eRAI therapy, of which 11 were positive and showed lesions in thyroid
bed and metastatic lesions in the neck nodes, lung, skeleton, and liver. Post eRAI
therapy, I 131 scan was positive in four patients, two showing neck uptake only, one
showing bone and other liver metastasis. Among the 12 who had single-dose eRAI only,
six showed positive response, one had partial response, while the negative response
was seen in five patients. Of the four patients who received two doses of eRIA, one
showed partial response, while the remaining three had excellent response, however,
with persistent high Tg.
Table 4 Characteristics and response of patients who received empiric radioactive iodine
therapy (n=16)
Outcome at last follow-up
When the outcome of these patients was assessed at the last follow-up, 33 (51.6%)
had become NED. Spontaneous normalization of Tg was seen in 27 patients, whereas three
became NED after further RAI therapy and three after LN excision. The mean time to
become NED was 4.07 ± 1.99 years. Patients who had spontaneous drop in Tg were comparable
to the rest in terms of age, gender, time of becoming TENIS, time from last RAI therapy,
dose of RAI, and type of tumor. However, ATA high-risk category (4/27 vs. 16/37; P
0.004), Tg level >10 (4/27 vs. 25/37; P < 0.01), presence of distant metastasis (2/27 vs. 19/37: P < 0.01), and lymph node metastasis (9/27 vs. 25/37; P 0.007) were significantly lower
in this group.
Of the 20 PSD patients, 16 showed DM and four had persistent LN metastasis. Among
those with DM, 11 had progressive disease with increasing Tg and worsening structural
disease. Among the eight PBD patients, one had bone metastasis but on follow-up, all
showed a falling trend in Tg except one who showed a rise. The three ID patients showed
a falling trend in Tg.
Empiric radioactive iodine therapy and outcome
Although the short-term response to eRAI was encouraging (of the 20 treatments, 12
showing some form of response with falling Tg level), only two became NED/ID on the
last evaluation. Eleven continued to have PSD (two lymph nodal metastasis, two thyroid
bed lesions, and seven lung/bone metastases) and three died from progressive disease.
However, of these 16 patients, nine had undergone LN exploration and five had EBRT
as well later in the course. All these additional treatments could have influenced
the final outcome of these patients and hence, the independent impact of eRAI therapy
on outcome could not be assessed.
Thyroglobulin level and outcome
When Tg level at TENIS was <10 ng/mL, almost 70% became NED, but only 40% did so when
Tg was >10 ng/mL and this difference was statistically significant (P = 0.007). Among NED, spontaneous Tg drop was seen in 22/24 in Tg <10 compared to
5/9 patients in Tg >10, the difference being significant (P = 0.017). Moreover, DM was more common (41.4%) in Tg >10 compared to 17.1% in Tg
<10 group and this difference was also statistically significant (P = 0.03). When Tg level was <2 ng/mL, all 11 patients became NED (10 patients Tg dropped
spontaneously, while one patient had bone metastasis and Tg dropped after RAI treatment).
On the contrary, all seven patients with Tg level >100 ng/mL had persistent disease,
five with DM, and two with LN metastasis [[Figure 2 ]].
Figure 2 Thyroglobulin levels and outcome of thyroglobulin elevation and negative iodine scintigraphy
subgroup
Univariate analysis showed all factors except gender, time of TENIS, and type of tumor
associated significantly with unfavorable outcome [[Table 5 ]], but multivariate analysis showed that only DM was significantly associated with
unfavorable outcome (P = 0.002).
Table 5 Univariate analysis of factors associated with unfavorable outcome in thyroglobulin
elevation and negative iodine scintigraphy subgroup
Thyroglobulin level cutoff for predicting outcome
ROC curve analyses showed that the highest area under the curve in terms of best compromise
between sensitivity and specificity for unfavorable outcome (sensitivity – 68.8%;
specificity – 72.3%) was achieved at a stimulated Tg level >10.42 ng/mL [[Figure 3 ]]. Overall median survival was 112 months for this cohort. When PFS was calculated
using Kaplan–Meier method [[Figure 4 ]], a significant difference was noted (P = 0.03), with better PFS in those with Tg <10 ng/mL group (111 months) compared to
72 months for Tg >10 [[Figure 4 ]].
Figure 3 Receiver operating characteristic curve analysis demonstrating thyroglobulin cutoff
for unfavorable outcome
Figure 4 Comparison of progression-free survival in patients with thyroglobulin > 10 and thyroglobulin
< 10
American Thyroid Association risk category and outcome
ATA risk levels and Tg TENIS were used in combination for predicting the outcome on
the last follow-up [[Figure 5 ]]. Best results were seen when initial risk was low and Tg at TENIS <10 ng/mL, ten
out of 11 such patients having had spontaneous conversion to NED. One patient had
PBD, but the Tg level showed falling trend. On the other hand, when patients initially
fell into the high risk (20/64), the outcome was unfavorable even with a Tg of <10
ng/mL. Although NED occurred spontaneously in one patient, four others required additional
therapy. With high risk and Tg >10 ng/mL, only one patient became NED and the rest
had persistent and progressive disease. This kind of difference in outcome was not
very obvious in the intermediate-risk category.
Figure 5 Comparison of Tg TENIS group and outcome among American Thyroid Association low.
and high-risk categories. Tg: Thyroglobulin, TENIS: Thyroglobulin elevation and negative
iodine scintigraphy
Discussion
The present study evaluated a subgroup of 64 patients with DTC and negative neck US,
who had become TENIS at different periods of follow-up. The prevalence of this TENIS
subgroup in this DTC cohort was comparable with that of TENIS from other publications.
This study population, however, was different from conventional TENIS since, by a
negative US, we largely eliminated local disease which could be managed differently.
Patients showed similar age and gender distribution compared to our general DTC patients.[[9 ]] The distribution of tumor types was not different either. However, when ATA risk
categories were compared with our general DTC cohort, more TENIS patients had high
risk (29.5% vs. 8.9%) and less, low risk (24.5% vs. 41%).[[9 ]]
One important finding of this study is that normalization of Tg level is possible
in nearly 50% of US neck negative TENIS patients and majority did so spontaneously.
Although not from a similar TENIS subgroup, Pacini et al . found that 67.9% of untreated TENIS patients normalized Tg and no structural disease
ever appeared in these patients on follow-up.[[5 ]]
In addition, the present study showed that a Tg cutoff at TENIS of 10.4 ng/mL can
be helpful in predicting the long-term outcome in this subgroup. A value above this
cutoff predicted the possibility of PSD and disease progression. The cutoff for Tg
level of 10.4 ng/mL in the present study validates the ATA recommendation that one
dose of eRAI can be given when Tg is >10 ng/mL and rising.[[10 ]] PFS in our patients is also significantly better with a Tg <10. However, the best
prediction of outcome in our cohort was on combining ATA risk category and Tg level
[[Figure 4 ]]. This shows the importance of considering the initial risk category along with
Tg level in determining the follow-up of this TENIS subgroup.
Compared to the general DTC cohort, where no patients died (236 patients with DTC
with median follow-up 53 months), three disease-specific deaths occurred in this small
cohort (4.6%) suggesting that our TENIS subgroup represents a form of aggressive DTC
requiring meticulous follow-up and aggressive management.[[9 ]] Although eRAI therapy was associated with poor outcome in this cohort, it may be
due to the fact that most of these patients fell in the high-risk category and had
DM. We were unable to assess the independent effect of eRAI on the outcome as some
of these patients underwent EBRT or further surgeries which could have influenced
the outcome. This study, however, is not powered enough to make any strong conclusion
because of the small sample size. Tyrosine kinase inhibitors (TKI) could not be used
in many because of socioeconomic reasons.
Strengths and limitations
The strength of this study is the uniqueness of dealing with a rare clinical entity,
with reasonable follow-up period without much dropouts. The addition of neck US before
considering eRAI which was not done in many such studies helps to make management
cost-effective in our resource-limited setting. The study findings have improved our
understanding of the course and outcome of TENIS patients in this part of the world.
The added strength of this study is the use of ATA recurrence risk stratification
along with Tg level in deciding the management strategy. Larger studies will be needed
for confirmation.
Limitations include the retrospective nature and small sample size, especially those
given eRAI which precluded subgroup analysis. Moreover, FDG PET/CT scans could not
be performed for all patients due to socioeconomical reasons and hence, the PET positivity
of TENIS and its influence on outcome could not be fully assessed.
Conclusion
The present study showed that patients with TENIS and a negative neck US who have
Tg at TENIS <10 ng/mL should do well and can be maintained on follow-up, especially
if they fall into the ATA 2009 low-risk category. On the other hand, when these patients
belong to the high-risk category and with Tg >10 ng/mL, they need to be closely followed
and periodically imaged for disease progression. DM portends unfavorable outcomes.
eRAI given to such high-risk patients did not benefit the outcome. Other than the
Tg cutoff of 10 ng/mL, the ATA risk category can possibly help to predict the outcome,
but larger studies are needed for confirmation. In those who show poor response to
eRAI, early consideration should be given for other modes of therapy such as TKIs,
EBRT, and metastases resection.
