ORIGINAL ARTICLE

Should patients with remnants from thyroid microcarcinomareally not be treated with iodine-131 ablation?

Rosj Gallicchio • Sabrina Giacomobono • Daniela Capacchione •

Anna Nardelli • Francesco Barbato • Antonio Nappi •

Teresa Pellegrino • Giovanni Storto

Received: 23 January 2013 / Accepted: 20 March 2013 / Published online: 28 March 2013

� Springer Science+Business Media New York 2013

Abstract Remnant ablation by radioiodine is generally

not recommended in patients presenting uni- or multifocal

cancer\1 cm, in the absence of other higher risk features.

We retrospectively studied low-risk patients (pts) with

differentiated thyroid cancer (DTC) less than 1 cm

recruited for radioiodine therapy (RAI). Methods: 91 pts

(79 women, age 48.4 ± 12 yrs) with DTC were enrolled

for RAI. Patients underwent pre-therapy ultrasonography

(US), those with suspected/ambiguous lymph-nodes were

excluded and proposed for cytology. Treated pts underwent

post-therapeutic whole body scan (WBSt) completed by

neck/chest SPECT/CT, when necessary (e.g. evidence of

uptake outside of thyroid bed). A target lesion on SPECT/

CT was defined as an identifiable lymph-nodal site pre-

senting a matched significant iodine uptake. The patients

were followed up for 14 ± 2 months thereafter. Results:

All pts/cancers were pT1. The mean histological diameter

was 0.68 ± 0.23 cm. Six patients were excluded because

of suspected nodal involvement at US. Thirty (35 %) out of

85 pts had suspicious WBSt as per lymph-nodal involve-

ment which was confirmed at the subsequent SPECT/CT

acquisition in most part of pts (26/30; 86 %). Overall

detected target lesions was 34, and nine (26 %) had interim

positive fine needle cytology. Conclusions: a significant

part of low risk DTC patients, for whom RAI is not

recommended, presents an incidental suspicion of lymph-

nodal involvement at WBSt confirmed by subsequent

SPECT/CT. Such setting would have not been treated by

I-131.

Keywords Radioiodine therapy � Remnant ablation �Differentiated thyroid cancer � Microcarcinoma �Low-risk patients

Introduction

The incidence of the epithelial derived thyroid cancer, also

known as differentiated thyroid cancer (DTC), is rising

[1, 2]. It represents about 80 % of all thyroid neoplasms

and it is optimally treated with thyroidectomy and func-

tional lymph node dissection, followed by radioiodine

ablation (RAI). As a result, DTC is among the most curable

cancer types [3, 4] whilst becoming a distressing disease

for those patients who suffer from unknown metastases,

recurrences or even relapse [5, 6]. Post-surgery radioiodine

treatment may constitute an irreplaceable support in the

therapeutic algorithm of these patients. Benefits have been

shown while the advantage seems to be mainly restricted to

patients with tumours [1.5 cm, or with residual disease

after the surgery. In addition, total thyroidectomy followed

by RAI therapy and aggressive thyroid hormone suppres-

sion therapy predicts an improved overall survival in

patients with intermediate/higher stage disease. On the

other hand, RAI for remnant ablation of DTC is not rec-

ommended for patients with uni- or multifocal cancer

\1 cm without other higher risk features being at lowest

risk for mortality. In such setting, it would not be beneficial

[7–9]. Several histological and clinical features have been

extensively weighted for placing the patients at higher risk

R. Gallicchio � S. Giacomobono � D. Capacchione �F. Barbato � A. Nappi � G. Storto (&)

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS),

Centro di Riferimento Oncologico di Basilicata (CROB),

Via P. Pio 1, 85028 Rionero in Vulture, Italy

e-mail: giosto24@hotmail.com

A. Nardelli � T. Pellegrino

Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle

Ricerche (CNR), Naples, Italy

123

Endocrine (2013) 44:426–433

DOI 10.1007/s12020-013-9935-9

of local recurrence or metastases [10]. Nevertheless, a

selective criterion that one dimensional, adopted to stratify

the patients who have to undergo RAI may reveal draw-

backs. In fact, it has been recently pointed out that in

patients presenting micropapillary thyroid cancer, the

locoregional recurrence is common and the lack of radio-

active iodine therapy may be associated with reduced

survival in stage I patients [11, 12]. As a result, controversy

exists regarding the optimal surgical treatment and the role

of adjunctive radioiodine [13] being the benefits of RAI

continuously debated in such setting. Our study was

undertaken to retrospectively evaluate the effects of per-

forming RAI in low-risk patients for whom the treatment

was scheduled irrespective of primary lesion’s histological

diameter (\1 cm).

Materials and methods

Patients

Ninety-one patients (79 women, age 48.4 ± 12 years,

range 17–76 years) with DTC were referred for RAI

4 ± 2 months after the total thyroidectomy and central

lymphadenectomy, if any, between 2008 and 2011. Fifty-

eight patients (64 %) presented unifocal cancer, whereas

33 had a multi-focal tumour.

All patients had undergone comprehensive clinical,

haematological/hormonal and instrumental evaluation at

baseline, before RAI, by means of physical examination

during scheduled visits, blood sample (TSH, thyroid hor-

mones and HTg; abHTg), neck ultrasound (US), chest

radiograph, EKG, pre-therapy remnant scan and measure-

ment of thyroid bed uptake. Pre-therapy serum thyroglob-

ulin (HTg) and AbHTg, whilst off L-thyroxine therapy for

4 weeks, were assessed. Serum HTg was measured using

an electrochemiluminescence immunoassay (ECLIA,

Roche Diagnostics GmbH, Mannheim, Germany), with a

functional sensitivity measuring a range of 0.1–1,000 lg/L,

a normal range of 1.4–78 lg/L, a within-run coefficient of

variation (CV) of 1.5 % and a total CV of 2.5 %.

All patients who underwent RAI signed an informed

consent form in accordance with the Declaration of

Helsinki.

Treatment procedure

I-131 therapy was carried out when the TSH rose ade-

quately (C25–30 mIU/L) after L-thyroxine withdrawal.

The I-131 activities administered ranged from 3,700 to

4,440 MBq (mean 3,733 ± 297). Patients were instructed

to observe low-iodine diet during 4 weeks and to avoid

possible iodine exposure (e.g. amiodarone use) as well as

pre-therapeutic iodine-131 scanning and/or iodine contrast

enhanced CT.

Measurement of iodine excretion with a spot urinary

iodine determination was routinely performed and preg-

nancy excluded.

Imaging modalities

Pre-therapy US examinations were performed with a GE

Logiq 9 machine (General Electric Company), a commer-

cially available real-time US system, equipped with a 9–14

and 6–8 MHz linear array transducer. On the detected

lymph-nodes hypoechogenicity, the presence of irregular

peripheral halo, microcalcifications, loss of the fatty

hyperechoic hilum and an intra-nodular vascularity were

considered criteria for abnormality [10]. When such criteria

were fulfilled, patients were excluded and a fine needle

biopsy was proposed.

Pre-therapy uptake in thyroid bed (7.4 MBq, os) was

evaluated quantitatively by means of remnant I-131 uptake

evaluation (Isomed 2162, Nuklearmedizintechnik, Dres-

den, Germany) and qualitatively at remnant planar scin-

tigraphy (Infinia VC Hawkeye 4, GE Milwaukee, WI,

USA). Patients underwent post-therapeutic whole body

scan (WBSt) completed by neck/chest single photon

emission computed tomography-computed tomography

(SPECT/CT) when necessary (e.g. evidence of uptake

outside of thyroid bed).

WBSt was performed 120 h after RAI using a dual-head

large field gamma-camera (Infinia VC Hawkeye 4, GE

Milwaukee, WI, USA) equipped with high energy colli-

mators (speed 8 cm/min; matrix 256 9 1024, averaged

collected counts 30,000 Kcts). The scan was acquired with

the patient in the supine position, removing attenuating

articles and with an instruction to the patients to remain

motionless.

SPECT/CT fusion imaging was performed, when

required, with a commercial SPECT scanner (Infinia VC

Hawkeye 4, GE Milwaukee, WI, USA) combined with a

four slice Helical CT system. (Zoom 1; Matrix 128 9 128;

Scan mode 40 s/step; rotation 360�; view angle 6�; 60

views, averaged collected Kcounts 40,000). CT (pitchx 1.9.

2.5 mAs. 140 kVp) was performed without intravenous

or oral contrast medium as part of SPECT/CT scan. The

raw CT data were reconstructed into transverse images

with a 5.0-mm section thickness. Sagittal and coronal CT

images were generated by reconstruction of the transverse

data.

Raw SPECT data were reconstructed iteratively with

and without attenuation correction into transverse, sagittal

and coronal images. Attenuation correction was based on

the CT attenuation coefficients, which were determined by

Endocrine (2013) 44:426–433 427

123

iterative reconstruction. All images were reviewed at

a workstation by using SPECT/CT fusion software

(Volumetrix for Hawkeye, GE). Each set of images was

interpreted by two experienced (15 years of expertise)

nuclear physicians in consensus. A target lesion in the

SPECT/CT study was defined as an identifiable lymph-

nodal site with soft-tissue/mediastinal window settings

presenting a matched significant iodine uptake. Then it was

assigned to the appropriate nodal level. Every focal I-131

uptake matching with normal anatomy or physiology (i.e.

salivary glands) as well as with thyroid tissue due to

remnant or ectopy, was excluded from this analysis.

Patients with inflammatory uptake were excluded too (i.e.

dental disease).

Follow-up diagnostic WBS was carried out 48 h after

oral administration of 185 MBq of I-131 using the same

dual-head large field gamma-camera and collimators

(speed 5 cm/min; matrix 256 9 1024, averaged collected

counts 600 Kcts).

Response assessment and clinical short-term follow-up

The first follow up (FU) was scheduled at 14 ± 2 months.

Results from physical examination during scheduled visits

were correlated to HTg dosage, abHTg and diagnostic

WBS findings after L-thyroxine withdrawal. A neck US

was also performed. Results from FNAC, if any, were

registered. On thin-layer cytology, the presence of epithe-

lial cells from lympho nodes specimen in combination with

immunohistochemical positivity for cytokeratin and HTg

was considered consistent with metastases from DTC.

A short-term response to RAI was defined as a complete

resolution of I-131 uptake in remnant and in a previously

detected target lesion within the neck/chest region, indis-

tinguishable from surrounding normal tissues and the

presence of undetectable HTg values (i.e. less than 1 lg/L)

and normal abHTg.

No treatment other than RAI was administered between

the baseline and the follow-up examinations.

Statistical analysis

Data are expressed as the mean ± 1 standard deviations, as

appropriate. Differences between the mean values were

assessed by Student’s t test (two-tailed probability) for

paired and unpaired data. Post hoc analysis with Bonferroni

correction was performed. Receiver-operator-curve (ROC)

analysis was carried out to estimate the optimal dimen-

sional cut-off of primary tumour for discriminating patients

who presented lymph-nodal metastases from those who did

not. A probability (p) value \0.05 was considered statis-

tically significant.

Results

All patients had total thyroidectomy, none had near-total,

and 24 had a systematic central lymphadenectomy. Histo-

logical specimens revealed papillary cancer in 83 pts and

follicular in two, without evidence of metastatic lymph-

nodes. None had aggressive histology such as tall cell,

insular and columnar cell carcinoma or vascular invasion.

Thirty pts had multifocal cancer (all foci \1 cm), whereas

16 presented minimal intrathyroidal invasion. All were

classified as pT1. Mean histological diameter was

0.68 ± 0.23 cm.

Patient baseline evaluation

Most of the patients did not show lymph-nodal involve-

ment on pre-therapy US and/or pulmonary concern on

chest-Xray. However, six pts were excluded because of

suspected/ambiguous lymph-nodes at US and proposed for

a fine needle biopsy.

Pre-RAI off-therapy serum HTg values ranged from 0.1

to 52.6 lg/L; mean 4.67 ± 6.7 lg/L. AbHTg(s) were

32.3 ± 99 UI/mL. The amount of thyroid bed uptake at 2 h

was 2.84 % ± 1.7 and at 6 h was 3.40 % ± 2.8. Remnant

scan was positive in all patients (significant iodine uptake).

WBSt and SPECT/CT assessment after RAI

Thirty (35 %) out of 85 enrolled patients had suspicious

findings at WBSt as per lymph-nodal involvement because

of the evidence of focal uptake outside of the thyroid bed,

in the neck (latero-cervical/loco-regional) and/or medias-

tinal regions (Table 1). None had received lymphadenec-

tomy. No distant metastases were detected.

Ten out of 30 (33 %) patients with multifocal cancer and

5/16 (31 %) among those with minimal intrathyroidal

invasion had lymph nodal involvement.

A SPECT/CT acquisition was performed consequently

in this setting and the presence of identifiable lymph-nodes

with matched significant iodine uptake was confirmed in

26/30 (86 %) patients (Figs. 1, 2). In the remaining four

patients, no target lesions were confirmed on SPECT/CT

because of the focal I-131 uptake matched with normal

anatomy or physiology (i.e. salivary glands).

According to age,\45 versus[45 years, the SPECT/CT

was positive in eight patients (31 %) and 18 (69 %),

respectively, whereas the four patients with negative

SPECT/CT were \45-years-old. Sixteen patients (62 %)

with positive SPECT/CT exhibited a unifocal cancer and

10 (38 %) had a multifocal tumour. The patients with

negative SPECT/CT presented unifocal DTC.

Overall detected target lesions was 34 (Table 1). Ten

patients underwent a meantime lymph nodal FNAC

428 Endocrine (2013) 44:426–433

123

(5 ± 1 month after RAI) because of a referral physician

decision and nine (9/34; 26 %) showed involvement from

the primary DTC. However, no re-intervention was rec-

ommended awaiting the 1-year FU appraisal.

ROC analysis (Fig. 3) recognised that the dimension of

seven millimetres for the primary tumour was the optimal

cut-off for differentiating patients who presented lymph-

nodal metastases from those who did not.

Clinical and instrumental follow up

The FU was carried out in all patients. None of them

complained about disease relapse with satisfactory global

performance status on L-thyroxine therapy. None of the

patients who performed follow-up by WBS off L-thyroxine

therapy demonstrated remnant or disease relapse in the

previously detected target lesions. The HTg values off

L-thyroxine therapy were 0.47 ± 0.52 lg/L (p \ 0.01 vs.

pre-therapy values). Final neck US was negative.

Discussion

Several studies have suggested the usefulness of I-131

remnant ablation for reducing disease recurrences and

cause-specific mortality in high/intermediate risk patients

with DTC [8, 14–16]. This therapeutic approach appears

to determine few advantages amongst most of the patients

with thyroid neoplasms who are at lower risk. How-

ever, the role of the adjunctive radioiodine in total

thyroidectomy and the benefits from RAI are being con-

tinuously disputed in this last setting [8, 13, 17, 18] since

no prospective studies have addressed this issue so far

[17].

Table 1 Individual data of low risk patients undergoing radioiodine therapy with lymph node involvement at scintigraphy

Pts

ID

Age Gender Histology Diameter

(cm)

Primary

lesion

characteristics

Baseline

HTg

(lg/L)

Baseline

Ab HTg

(UI/mL)

Disease

detection

on WBSt

Disease

detection on

SPECT/CT

Target

lesions

(n)

Nodal

level

2 58 F P 0.7 M 52.6 0.8 ? ? 3 VI/III

4 49 F P 0.5 I 2.4 2.3 ? ? 1 VI

8 39 F P 0.7 M 4 51.1 ? ? 1 VI

12 17 F P 0.8 M 8.7 1.6 ? ? 2 VI

17 52 F F 1 I 0.3 21.1 ? ? 1 VI

18 29 M P 0.8 I 1.1 5.8 ? ? 1 VI

27 73 F P 0.4 M 6.7 0.6 ? ? 1 III

30 55 F P 0.3 I 1.6 12.3 ? ? 1 VI

31 55 F P 0.7 U 32.2 2.2 ? ? 2 VI/III

35 26 F P 1 I \0.2 21.7 ? ? 1 VI

44 45 F P 0.8 U 1.6 3.2 ? ? 1 VI

45 54 F P 0.9 U 5.2 12.1 ? ? 2 VI

47 65 F P 0.5 M 10.9 3.7 ? ? 1 VI

52 46 F P 0.8 U 31.6 4.1 ? ? 1 III

54 62 F P 0.1 U 8.8 2.8 ? ? 1 VI

56 38 F P 0.8 U 2.1 267 ? ? 1 VI

61 45 F P 0.7 M 11.2 17.7 ? ? 2 VI/III

63 45 M P 0.6 U 9.1 1.4 ? ? 1 VI

67 40 F P 0.7 M 25.8 3.3 ? ? 1 VI

68 53 F P 0.4 U 1.2 207 ? ? 1 VI

69 40 F P 0.7 U 17.6 5 ? ? 2 VI/III

72 69 F P 0.9 U 1 10.1 ? ? 1 VI

74 40 F P 0.7 M 4.7 9.3 ? ? 2 VI/III

77 53 F P 0.4 U \0.2 54.05 ? ? 1 VI

78 76 M P 0.3 M 23.9 1.2 ? ? 1 III

83 53 F P 0.25 M 0.9 51.7 ? ? 1 VI

HTg serum thyroglobulin, Ab Htg anti-thyroglobulin antibodies, WBSt therapeutic whole body scan, SPECT/CT single photon emission com-

puted tomography/computed tomography, P papillary thyroid cancer, F follicular thyroid cancer, M multifocal microcarcinoma, I intrathyroidal

minimal invasion, U unifocal

Endocrine (2013) 44:426–433 429

123

The most recent guidelines [10, 19] do not recommend

thyroid remnant ablation for low-risk group of patients

with unifocal DTC smaller than 1 cm when the extension

beyond the thyroid capsule is excluded. On the other hand,

they still opine on whether iodine-131 has to be adminis-

tered to all or only to selected patients. The ATA guide-

lines [10, 20] have confirmed that the omission of

radioactive iodine in the therapeutic algorithm does not

correlate with reduced survival in stage I patients.

The data from our study suggest that a part of low risk

patients with DTC, usually classified as micro-carcinoma,

present a suspected lymph-nodal involvement in WBSt,

with most of the target lesions confirmed when a sub-

sequent SPECT/CT imaging is performed. This setting

would have not been treated by I-131, essentially because

of primary lesion dimension, influencing almost certainly

the prognosis.

Despite node metastases being present in up to 50 % of

cases, also in small tumours, the frequency of positive

lympho node imaging in micro DTC appears to be lower,

even if it has been substantially fixed by US which fails to

detect approximately 50 % of metastatic nodes [21, 22]. In

fact, advocates of prophylactic central node dissection

highlight the improved number of lympho node metastases

Fig. 1 SPECT/CT images of a

low-risk patient undergoing

RAI who incidentally showed

lymph node involvement at the

superior mediastinal aditus (VI

level). a CT images. b SPECT

images. c Hybrid/fusion images

430 Endocrine (2013) 44:426–433

123

and the insufficient diagnostic accuracy of US and intra-

operative exploration in 1/3 of DTC patients [23, 24]. As a

result, new diagnostic tools, before and during RAI, are

being continuously implemented in order to facilitate the

disease characterisation (see PET/CT and SPECT/CT).

Our patients had negative US and positive I-131 uptake

matching (on SPECT/CT) with a central/latero-cervical

lympho node, or at least, with a lympho node location, which

endorses the concept that thyroid wondering cells (metas-

tases) may have colonised this level in a sufficient number,

despite the absence of clearly detectable morphological

alterations. Thus, the SPECT/CT technology is supposed to

be more accurate by reason of the availability of co-regis-

tered images [25]. This nuclear medicine methodology has

been referred to as a suitable tool for staging, follow-up and

tumour response assessment in oncological patients [26]

since it offers the advantage of a functional tissue charac-

terisation combined to a morphological appraisal.

Our findings, similarly to others, [27] suggest that DTC

1 cm or smaller in diameter are of little clinical risk but not

risk-free. The size of thyroid tumour is an independent pre-

dictor of outcome [16] and the risk estimate has been made

according to a fixed cut point [28] above which adverse

events increase statistically. However, this approach does

not provide a clear representation for the smallest thyroid

tumours that can produce metastases [29]. In fact, some

authors have estimated the cumulative risk according to

tumour growth and reported that the threshold for developing

an extrathyroidal tumour spread and lymph node metastases

was 5 mm for papillary cancer and 20 mm for follicular,

even if none of the patients died of thyroid cancer [30]. All

our patients had a less than 1 cm primary lesion and the

current threshold to discriminate patients having lymph-

nodal concern from those who did not was 7 mm.

Fig. 2 SPECT/CT images of low-risk patients (#52 and #78) undergoing RAI who incidentally showed latero-cervical lymph node involvement

(III level for both). a CT images. b SPECT images. c Hybrid/fusion images

Fig. 3 Received operator curve to assess the optimal dimensional

cut-off of the primary tumour for differentiating patients who

presented lymph-nodal metastases from those who did not

Endocrine (2013) 44:426–433 431

123

This study substantiates further that an incidental

lymph-node involvement (confirmed cytologically in 26 %

of target lesions) may be detected also in low risk patients

with micro-DTC giving rise to the need for completion of

surgical therapy by RAI in selected patients [31–33]. Our

findings are similar, in the quintessence, to those from

Pelizzo et al. [12]. These authors, on a series of 403

patients, reported an associated node dissection to thy-

roidectomy in 127 patients in whom a micro-DTC was

diagnosed preoperatively or in whom suspected lympho

node metastases were found only at intervention. At

operation, lympho node metastases were found in 47/127

(37 %). In our setting, the 26 patients (30 %) who pre-

sented a SPECT/CT lympho node involvement (mostly VI

level) did not receive a node dissection, neither suspected

nodes were found on US.

Considering the multifocal micro-DTC, when all foci are

\1 cm, recent data suggest that RAI is of no benefit in

preventing recurrence [13, 34]. However, multiple intra-

thyroidal tumours are associated with an increased risk of

loco-regional and/or distant metastases and enduring dis-

ease, all suggesting the need for RAI [15, 35, 36], in some

conditions. Our study showed a lymph node concern in ten

of 30 patients with a multifocal microcarcinoma.

All patients underwent short-term follow-up (which is

the only available option in this setting) and exhibited a

complete remission also by means of a sensitive thyro-

globulin assay. These data are similar to those of Bonnet

et al. [23] who reported that 1 year after surgery, no

patients showed suspicious LN on US and HTg levels were

undetectable in 97,4 % of all cases treated with radioio-

dine. Conzo et al. [24] have recently described that

6 months after RAI, also for micro-DTC, cervical US was

negative and HTg levels \1 ng/mL.

Conclusion

A large part of low risk patients with micro-DTC (\1 cm),

for whom RAI is not recommended, present an incidental

suspicion of lymph-nodal involvement at WBSt for the

most part confirmed by subsequent SPECT/CT. This set-

ting would have not been treated by I-131.

Indications for RAI in DTC low risk patients could be

revised at least re-considering the dimensional cut-off for

the primary lesion and the contributions from new diag-

nostic tools. However, the results from our study need to be

confirmed on larger series.

Acknowledgments This research did not receive any specific grant

from any funding agency in the public, commercial or not-for-profit

sector.

Conflict of interest The authors have indicated they have no

financial conflicts of interest.

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