Lau et al.

Thyroid Research (2021) 14:3

https://doi.org/10.1186/s13044-021-00094-1

RESEARCH Open Access

Malignancy risk of hyperfunctioning thyroid

nodules compared with non-toxic nodules:
systematic review and a meta-analysis
Lorraine W. Lau1,2, Sana Ghaznavi1,2, Alexandra D. Frolkis1, Alexandra Stephenson3, Helen Lee Robertson4,
Doreen M. Rabi2,5 and Ralf Paschke1,2,6*

Abstract
Background: Hyperfunctioning or hot nodules are thought to be rarely malignant. As such, current guidelines
recommend that hot nodules be excluded from further malignancy risk stratification. The objective of this
systematic review and meta-analysis is to compare the malignancy risk in hot nodules and non-toxic nodules in
observational studies.
Methods: Ovid MEDLINE Daily and Ovid MEDLINE, EMBASE, Scopus, and Web of Science databases were searched.
Observational studies which met all of the following were included: (1) use thyroid scintigraphy for nodule
assessment, (2) inclusion of both hyperfunctioning and non-functioning nodules based on scintigraphy, (3) available
postoperative histopathologic nodule results, (4) published up to November 12, 2020 in either English or French.
The following data was extracted: malignancy outcomes include malignancy rate, mapping of the carcinoma within
the hot nodule, inclusion of microcarcinomas, and presence of gene mutations.
Results: Among the seven included studies, overall incidence of malignancy in all hot thyroid nodules ranged from
5 to 100% in comparison with non-toxic nodules, 3.8–46%. Odds of malignancy were also compared between hot
and non-toxic thyroid nodules, separated into solitary nodules, multiple nodules and combination of the two.
Pooled odds ratio (OR) of solitary thyroid nodules revealed a single hot nodule OR of 0.38 (95% confidence interval
(CI) 0.25, 0.59), toxic multinodular goiter OR of 0.51 (95% CI 0.34, 0.75), and a combined hot nodule OR of 0.45 (95%
CI 0.31, 0.65). The odds of malignancy are reduced by 55% in hot nodules; however, the incidence was not zero.
Conclusions: Odds of malignancy of hot nodules is reduced compared with non-toxic nodules; however, the
incidence of malignancy reported in hot nodules was higher than expected. These findings highlight the need for
further studies into the malignancy risk of hot nodules.
Keywords: Thyroid nodules, Malignancy, Hot nodule, Thyrotoxicosis, Thyroid cancer

* Correspondence: [email protected]
1
Department of Medicine, Cumming School of Medicine, University of
Calgary, Calgary, Canada
2
Section of Endocrinology and Metabolism, Department of Medicine,
Cumming School of Medicine, University of Calgary, Calgary, Canada
Full list of author information is available at the end of the article

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Lau et al. Thyroid Research (2021) 14:3 Page 2 of 16

Background Methods
Autonomously hyperfunctioning thyroid nodules rep- Protocol and registration
resent approximately 5–10% of all thyroid nodules. This systematic review was registered with a pre-published
These so-called “hot nodules” are defined by in- protocol on PROSPERO (CRD42019119204). Reporting
creased radiotracer uptake compared to surrounding was in accordance with the preferred reporting items for
thyroid parenchyma on scintigraphy. Hot nodules can systematic review and meta-analyses (PRISMA) [18].
exist as a single hot nodule or as toxic multi-nodular
goiters (TMNG). The degree of autonomous hyper- Search strategy and databases
function in hot nodules is variable, and some hot Two investigators (LL & RP) created a preliminary search
nodules may not produce sufficient levels of thyroid strategy that was subsequently refined by a medical librar-
hormones to suppress TSH levels at initial presenta- ian (HLR). In brief, a search strategy aimed to include all
tion [1–4]. Clinical care pathways for the manage- articles from human studies published up to November
ment of thyroid nodules recommend measurement of 12, 2020 that utilized scintigraphy to assess functional sta-
serum thyrotropin (TSH) followed by scintigraphy in tus of thyroid nodules and subsequently included histo-
patients with the presence of thyroid nodules and pathologic data on these nodules. Complete search terms
subnormal TSH levels [5]. Scintigraphy use in patients are available in Supplemental Fig. 1. Citations were found
with normal TSH levels has been questioned [2] and by searching the following databases from the first date
is more commonly utilized in Europe [4]. available to November 12, 2020: Epub Ahead of Print, In-
Compared to non-toxic nodules, hot nodules are trad- Process & Other Non-Indexed Citations, Ovid MEDLINE
itionally believed to have an exceptionally low rate of Daily and Ovid MEDLINE, EMBASE, Scopus, and Web of
malignancy. This has led to widely-adopted recommen- Science. Combinations of subject headings, keywords and
dations by several guideline groups not to perform fine synonyms used included all three key terms: 1) thyroid
needle aspiration biopsy on these lesions irrespective of nodule, 2) hyperthyroidism, thyrotoxicosis, and hot nodule
their size [1–7]. However, recent studies have challenged and 3) thyroid neoplasm, thyroid carcinoma, medullary
the presumed low-risk of malignancy in hot nodules, carcinoma, follicular carcinoma, papillary carcinoma, and
suggesting that the incidence of cancer has been under- anaplastic carcinoma. The formalized search strategy is
estimated [6–10]. In 22 patients who underwent thyroid summarized in the Supplementary information.
surgery irrespective of functional nodule status, Ashcraft
and Van Herle reported a malignancy risk of 4% in hot Study selection
nodules [11, 12]. A recent study demonstrated higher than After duplicates were removed, two reviewers (LL & AS)
expected malignancy rates in hot nodules with an overall independently screened 1464 articles. Initial screen of the
malignancy rate of 8.5% [13]. The reported malignancy title & abstract for full text assessment was determined
rates of hot nodules ranges broadly from 0.34 to 44% based on mention of thyroid nodule functional status and
among patients undergoing thyroid surgery [14, 15]. In inclusion of surgical pathology. An additional 5 articles
comparison, the reported malignancy rate of non-toxic were added from other sources. These sources include re-
nodules ranges from 8 to 16% [7, 11–13, 16, 17]. view of references in published reviews and included arti-
Given the current recommendation against cytologic cles, and additional articles recommended by expert
evaluation of hot nodules, and the widely variable ma- researchers and clinicians in the field. Case reports, review
lignancy rate reported in these lesions, there is a need articles, and small series (n ≤ 10) studies were excluded.
to critically appraise the current literature in this Studies that included nodules noted outside the thyroid
area. Therefore, this systematic review aims to address gland were also excluded. Inclusion criteria included studies
the question: among those individuals undergoing thy- that used thyroid scintigraphy (131I/123I or T99m) for nodule
roidectomy for benign indication, are hot nodules di- assessment, inclusion of both hyperfunctioning and normo
agnosed by scintigraphy associated with a lower risk −/hypo-functioning nodules based on scintigraphy, avail-
of thyroid malignancy compared with non-toxic able postoperative histopathologic nodule results, and no
thyroid nodules? Secondary objectives include com- age restriction. The reviewers (LL & AS) independently de-
parison of malignancy risk in single compared with termined if studies met inclusion and exclusion criteria.
multiple hot nodules, assessment of reported carcin- Discrepancies were settled by a third reviewer (RP).
omas within compared to outside the hot nodule,
association of hyperfunctioning on scintigraphy com- Data extraction
pared with biochemical hyperfunctioning (as deter- Among the articles that met inclusion and exclusion cri-
mined by TSH levels) and its impact on malignancy, teria for analysis, the data extracted is summarized in
and the impact of inclusion of microcarcinomas on Supplemental Table 1. In brief, quantitative measures in-
malignancy rates of hot nodules. cluded sample size, gender distribution, number of hot
Lau et al. Thyroid Research (2021) 14:3 Page 3 of 16

nodules and non-hot nodules and distribution of thyroid and Review Manager 5.3 (Version 5.3.5, The Cochrane
carcinomas. Binary measures included clear description Collaboration, Copenhagen, Denmark).
of the thyroid carcinoma within the nodule, inclusion of
microcarcinomas, and presence of genetic mutations.
Data management was performed with Microsoft Excel. Quality assessment
Furthermore, incidence of malignancy was calculated for The methodological assessment of included cohort stud-
all hot nodules and non-toxic nodules. ies was assessed by two independent reviewers (LL, RP)
using the Newcastle-Ottawa Scale [21]. The role of this
Data analysis tool is to assess for patient selection bias, and for com-
Analyses were performed exploring the pooled odds ratio parability of study groups and study outcomes.
(OR) and 95% confidence interval (CI) of malignancy in:
1) single hot thyroid nodules compared with non-toxic
nodules based on scintigraphy; 2) toxic multinodular goi- Results
ters containing a hot nodule compared with non-toxic Search results
multinodular goiters; and 3) all hot nodules. Heterogeneity Our search results are summarized in Fig. 1. Among 2487
across studies was determined using Cochran’s Q and I2 citations identified for review, there were 1644 remaining
statistic [19]. Due to the presence of significant heterogen- after removal of duplicates. Upon review of title and
eity, Mantel-Haenszel-weighted DerSimonian and Laird abstract, 83 full text articles were reviewed. Based on our
random-effects model were utilized [20]. Meta-regressions exclusion criteria, 76 articles were excluded (reasons sum-
were not performed due to limited sample size. All ana- marized in Supplementary Tables 2 and 3) with 7 studies
lyses were performed using Stata 14.2 with an alpha of 0.1 included for qualitative and quantitative synthesis.

Fig. 1 PRISMA Study flow diagram. Summary of the search strategy results based upon a pre-determined inclusion and exclusion criteria. Seven
studies met criteria and their demographic data are summarized in Table 1
Lau et al. Thyroid Research (2021) 14:3 Page 4 of 16

Characteristics of included studies comparison to all non-hot nodules (OR = 0.45; 95% CI
A summary of the 7 observational studies included in 0.31, 0.65; I2 = 57%). These outcomes are summarized in
our synthesis is presented in Table 1 [9, 22–27]. Publica- Fig. 4.
tion dates ranged from 1994 to 2019. Studies originated Incidence of malignancy was calculated for all nodules
predominantly from Europe, with 2 of 7 from Italy and 2 and is summarized in Table 2. Among the 7 studies, the
of 7 from Turkey. Total number of thyroid nodules overall incidence of malignancy in all hot nodules ranged
across all studies was 7726, which ranged from 120 to from 5 to 100% in comparison with non-toxic nodules,
2870 nodules per study. Mean age ranged from 11.5 to ranging from 3.8–46%. The FNA cytology and surgical
54 years old. Overall, most studies were surgical cohort histology results are also summarized in Table 2.
studies that retrospectively examined predictors of ma-
lignancy. Thyroid carcinomas were diagnosed by fine Assessment of bias and quality of evidence
needle aspiration biopsy (FNAB) and/or surgical hist- Risk of bias was assessed using the Newcastle-Ottawa as-
ology. Scintigraphy was conducted with Tc99m in 5 of 7 sessment scale for cohort studies, which evaluated the
studies. In these five studies, scintigraphy was routinely quality of the evidence based on selection, comparability,
performed in all the patient cohorts. Microcarcinomas and outcome (Table 3) [21]. Only one study was
were reported in 5 of 7 studies. Microcarcinomas com- assessed as low risk with 6 stars; however, this study
prised between 9.5 to 100% of the carcinomas reported evaluated only pediatric patients [23]. All other studies
in the studies. Among the 7 studies, only two study pro- were assessed as having high risk of bias as they were all
vided clear localization of the thyroid carcinoma within surgical cohorts without a non-surgical (ie. medically
the hot nodule as these pediatric patients only had one managed) cohort for comparison, thus awarded 5 stars
nodule [23, 27]. In the other 4 studies, it is unclear if the or less. Furthermore, Mon et al. was assessed with high
carcinoma was confirmed within the hot nodule or in risk of bias in comparability as this study selected specif-
adjacent thyroid tissue. ically for patients with TSH receptor mutation without a
TSH level was measured in all studies. However, only mutation negative study control. Follow up duration and
two studies reported the TSH levels and correlated these adequacy were not applicable to the assessment.
levels with scintigraphy results [9, 23]. The three other
studies did not directly report TSH levels for hot nod- Post-hoc assessment of malignancy outcomes in studies
ules [22, 24–27]. reporting hot nodules only
Given the higher than expected incidence of malignancy
Malignancy rate in hot nodules in the included studies, studies that were excluded due
Hot nodules were differentiated into single hot nodules to lack of non-toxic nodules were re-examined. Specific-
and TMNG. Similarly, non-toxic nodules were differen- ally, the incidence of malignancy in hot nodules was
tiated into single non-toxic nodules (NTN) and non- evaluated in single hot nodules and TMNG. These find-
toxic multinodular goiters (MNG). Study outcomes for ings are reported in Supplementary Table 4. Quantitative
the odds ratio of single hot nodules versus single NTN assessment was not performed as the comparability of
are shown in Fig. 2. Pooled odds ratio in 5 studies in- the studies was not appropriate. Incidence of malignancy
volving 6778 nodules demonstrated a lower odd of ma- ranged from 0 to 44% in single hot nodules, 0–26% in
lignancy in single hot nodules (OR = 0.38; 95% CI 0.25, TMNG, and 0–29% in all hot nodules (single hot nod-
0.59; I2 = < 0.0002) compared to single NTN. Mon et al. ules and TMNG).
represented a distinct outlier with an OR of 5.50 (95% Furthermore, post hoc analysis of odds of malignancy
CI 0.23, 128.97) [9]. Malignancy rates are reported ma- in only adult patients without a prior knowledge of
lignancy per rates per nodule. Both Baser et al. and Tam TSHR mutations is summarized in Supplemental Fig. 1.
et al. were excluded as it was unclear whether nodules Pooled ORs of all hot nodules was lower than all non-
were solitary or MNG [22, 27]. toxic nodules (ORs 0.43, 95% CI 0.32, 0.58, I2 = 46%).
The pooled odds ratio of 4 studies involving 6658 indi-
viduals demonstrated a lower odd of malignancy in Case reports identified through the search strategy
TMNG compared to non-toxic MNG (OR = 0.51; 95% Based on our search strategy, 62 case reports of thyroid
CI 0.34, 0.75; I2 = 48.3%). These outcomes are summa- carcinoma within a hot nodule were identified with
rized in Fig. 3. Mon et al. was a clear outlier in compari- publication dates from 1972 to present. Demographic in-
son with the three other studies with an OR of 23 (95% formation was extracted from these case reports and are
CI = 0.61, 862.86) [9]. Corrias et al. was excluded from seen in Table 4. Patient age varied from 2 months to 74
this analysis as MNGs were absent in their study [23]. years of age. Most hot nodules were single hot nodules,
The overall pooled OR for all hot nodules, including though some TMNGs were also included. Papillary
both single and multiple nodules, was lower in thyroid carcinomas (PTCs) and follicular thyroid
 Lau et al. Thyroid Research
(2021) 14:3

Table 1 Characteristics of the 5 cohort studies included in qualitative and quantitative analysis
Authors Year Country Sample Mean Retrospective/ Diagnosis Radiotracer Inclusion of Carcinoma localized Hot nodule – Hot nodule –
Size Age Prospective method microcarcinomas (%) to hot nodule Hyperthyroida (%) Euthyroida (%)
Baser, H., et al. [22] 2019 Turkey 509 54.6 Retrospective FNAB/Histology Tc99m Yes (?) No Unknown Unknown
Corrias, A., et al. [23] 2010 Italy 120 11.5 Retrospective FNAB(104) /Histology Tc99m No Yes 67 33
(63)
Derosa, G., et al. [24] 1994 Italy 619 46.0 Retrospective FNAB/Histology Tc99m No No 100 0
Dirikoc, A., et al. [25] 2017 Turkey 2870 49.0 Retrospective Histology Tc99m/131I Yes (75.1%) No 100 0
Mon, S. Y., et al. [9] 2018 USA 703 48.6 Prospective FNAB Iodine Yes (9.5%) No 67 33
Slijepcevic, N., et al. 2015 Serbia 2466 54.0 Retrospective Histology Unknown Yes (100%) No Unknown Unknown
[26]
Tam, A., et al. [27] 2019 Turkey 439 46.0 Retrospective FNAB/Histology Tc99m Yes (?) Yes Unknown Unknown
a
Hyperthyroid defined as suppressed TSH, and euthyroid defined as normal TSH
Page 5 of 16
Lau et al. Thyroid Research (2021) 14:3 Page 6 of 16

Fig. 2 Pooled odd ratios for malignancy risk of single hot thyroid nodules compared with single non-toxic nodules based on scintigraphy

carcinomas (FTCs) were the most commonly reported need to explicitly report malignancy rates with and with-
malignancies. However, follicular variant of papillary out inclusion of incidental papillary microcarcinomas.
thyroid carcinomas (fvPTC), Hurthle cell, anaplastic Each of these issues will be discussed in detail below.
(with a concomitant hot nodule) and medullary thyroid
carcinomas (described as a cold area of the HN) were Location of the thyroid carcinoma within the hot nodule
also identified [28, 29]. A major challenge in the assessment of thyroid malig-
Among these 62 case reports, only two (4%) reported nancy, particularly in multinodular goiters, is the loca-
microcarcinomas within the hot nodules [30, 31]. In all 9 tion of the malignancy. It is not uncommon for a
pediatric studies, there was sufficient evidence to support malignant nodule to co-exist with a benign nodule
the presence of the thyroid carcinoma within the hot nod- within the same thyroid lobe. This challenge can also be
ule [31–39]. In the 53 adult studies, 49% of studies had applied to hot nodules. Schroder and Marthaler evalu-
sufficient evidence to demonstrate thyroid carcinoma ated 63 publications describing the presence of hot nod-
presence within the hot nodule [8, 29, 35, 40–63]. ules with concurrent follicular or papillary thyroid
cancer [64]. Out of the 63 publications, only 10 provided
Discussion unequivocal confirmation of the carcinoma within the
This systematic review and meta-analysis of observa- hot nodules, whereas in the other studies, it was uncer-
tional studies comparing the malignancy rate of hot nod- tain whether the malignancy was found within the hot
ules compared with non-toxic thyroid nodules nodule or an adjacent non-toxic nodule. Interestingly,
demonstrated a reduced malignancy rate in hot nodules; this study together with Pazaitou-Panaylotou et al de-
however, the rate was not as low as previously expected. scribed increased mortality in patients with carcinomas
Therefore, the findings of this review prompt us to ques- detected within the hot nodule [64, 65].
tion the widely adopted recommendation to avoid cyto- The identification of the carcinoma within the hot
logic evaluation of hot nodules, based on the belief that nodule can be technically difficult and requires close
hot nodules harbour a significantly lower malignancy interdisciplinary collaboration. Localisation of the thy-
rate than non-toxic nodules. Our findings cannot defini- roid carcinoma in a specific nodule is particularly diffi-
tively support or refute this recommendation; however, cult in multi-nodular thyroid glands. However, accurate
this review gives us important insight into the methodo- cytologic-histologic correlation of carcinomas is critical
logical and evidence limitations in this area of the to understanding the true malignant potential of hot
literature, including the need for meticulous cytologic- nodules [65]. Among the five studies included in this
histologic and imaging correlation of nodules, and the systematic review, Corrias et al identified the location of

Fig. 3 Pooled odds ratio for malignancy risk of toxic multinodular goiters (TMNG) containing a hot nodule compared with non-toxic
multinodular goiters
Lau et al. Thyroid Research (2021) 14:3 Page 7 of 16

Table 2 Reported incidence of malignancy in all nodules including hot nodules and non-toxic nodules
Authors Overall Overall Incidence of Incidence of Incidence of Incidence of FNA Biopsy Malignant
incidence of proportion of malignancy in malignancy malignancy malignancy results Surgical
malignancy (%) hot nodules (%) single hot in TMNG (%) in NTN (%) in MNG (%) Histology
nodules (%)
Baser, H., et al. 5 73 N/A N/A 3.8 6.6 80 – 8 – PTC
(2019) [22] Nondiagnostic 2 – FTC
259 – Benign 3 – TTUMP
17 – AUS/ 1 - UTC
FLUS
2 – FN/SFN
2 – SM
4 - Malignant
Corrias, A., 30 16 11 6 22 16 3 suspicious 1 - PTC (All 3
et al. (2010) suspicious FNAB
[23] were benign)
Derosa, G., 10 26 5 25 13 42 Not reported 8 - PTC
et al. (1994)
[24]
Dirikoc, A., 34 34 24 8 46 14 a
50 – 118 PTC 7 FTC 6
et al. (2017) Nondiagnostic Other
[25] 83 –
indeterminate
13 –
malignant
Mon, S. Y., 13 12 33 100 8 8 2 - Benign 2 FTC (Both were
et al. (2018) 1 - AUS/FLUS FNAB benign)
[9]
Slijepcevic, N., 16 6 7 14 16 21 Not reported 9 PTC
et al. (2015)
[26]
Tam, A., et al. 25 17 N/A N/A 10 28 8– 10 PTC
(2019) [27] Nondiagnostic 4 FTC
51 – Benign (7 malignancies
3 – AUS/FLUS located outside
2 – FN/SFN hot nodule)
1 - Malignant
TMNG toxic multinodular goiter, NTN non toxic nodule, MNG multinodular goiter, FNA fine needle aspirate, AUS/FLUS atypia of undetermined significance/follicular
lesion of unknown significance, SM suspicious for malignancy, PTC papillary thyroid cancer, FTC follicular thyroid cancer, TTUMP thyroid tumour of unknown
malignant potential, UTC undifferentiated thyroid cancer, Other includes Hurthle cell, medullary or undifferentiated
a
Denotes cytology findings in all hyperthyroid patients

the carcinoma [23]. This study differed from the other cannot be extrapolated to the adult population [66]. In
four studies in that only pediatric patients were included. all 9 pediatric case reports there was sufficient evidence
Given the increased malignancy risk reported in to support the presence of the thyroid carcinoma within
pediatric thyroid nodules compared to the adult popula- the hot nodule as there was a single hot nodule being in-
tion, malignancy rates found in pediatric populations vestigated, which correlated to location of the carcinoma

Fig. 4 Pooled odds ratio for malignancy risk for all hot nodules including thyroid glands with single or multiple nodules
Lau et al. Thyroid Research (2021) 14:3 Page 8 of 16

Table 3 Summary of risk of bias assessment based on Newcastle-Ottawa Quality Assessment for Cohort Studies. A filled star denotes
that a star has been awarded and that a study has been graded high quality. A blank star denotes that no star has been awarded
and that the study has been graded as poor quality in that category. Total score indicates the total number of stars awarded in all
categories. N/A denotes not applicable

on pathology [31–39]. In the 53 adult studies, nearly half nodules [73]. A clear outlier in this review is a study that
(49%) of the studies demonstrated sufficient evidence of deliberately selected indeterminate nodules with TSHR
the thyroid carcinoma within the hot nodule based on mutations identified by molecular diagnostic testing of in-
the presence of a single hot nodule on scintigraphy with determinate thyroid nodules [9]. Among the 16 TSHR
the location of the carcinoma on pathology [8, 29, 35, mutation positive patients with available histology, 3 pa-
40–63, 67–70]. The other case reports were confounded tients had evidence of thyroid cancer. This study repre-
by the presence of multiple thyroid nodules, and did not sents a highly selected group with an unusual way of
clearly delineate the location of the hot nodule on scin- diagnosing hot nodules that is very distinct from the other
tigraphy with pathology. study populations. A major deficiency in this study is the
lack of appropriate clinical diagnosis of hot nodules prior
Inclusion of microcarcinomas to FNA and molecular diagnostics. TSH was only mea-
The percentage of carcinomas that were microcarcinomas sured in 27 of the 703 thyroid samples tested for muta-
in the seven included studies ranged from 9.5 to 100%. tions and rearrangements and scintigraphy was used in
The increased detection of papillary thyroid microcarcino- only 4 of the 6 patients with suppressed TSH. Thus, the
mas (defined as tumours less than or equal to 10 mm) has OR for this group cannot be generalized for hot nodules.
contributed significantly to the rise in incidence of thyroid
cancer over the last few decades [71]. Microcarcinomas
can be found in up to 35% of post-mortem studies [72]; Limitations
most of these lesions are believed to be clinically The notion that hot nodules rarely harbour malignancy
insignificant. This has led to the current American Thy- is based on studies conducted in the 1960s to 1980s that
roid Association (ATA) recommendation to monitor examined scintigraphy in an undifferentiated patient
sonographically suspicious or biopsy-proven papillary population with thyroid nodules [12, 74]. At that time,
microcarcinomas, in an effort to prevent over-diagnosis the prevalence of thyroid nodules was estimated at 4 to
and over-treatment of asymptomatic disease. In future 7% in the general adult population, with the risk of ma-
studies, these low-risk microcarcinomas should either be lignancy ranging from 10 to 20% [75, 76]. Since then,
analyzed separately, or excluded from the analysis of ma- the prevalence of thyroid nodules has increased to 19–
lignancy rate, to reflect the true risk of clinically significant 67% of the adult population based on increased use of
malignancy in the study population. and advances in ultrasonography, with similar malig-
nancy rates of 8–16% [17, 77].
Mon et al. as the study outlier A wide variation of incidence rate of malignancy was
The use of molecular diagnostics is gaining increasing rec- reported in both hot nodules and non-toxic nodules in
ognition in the assessment of indeterminate thyroid our study. A major confounder in all studies was the
Lau et al. Thyroid Research (2021) 14:3 Page 9 of 16

Table 4 Summary of 62 case reports identified through our search strategy that reported thyroid carcinomas within hot nodules.
(AFTN autonomously functioning thyroid nodules, TMNG toxic multinodular goiter, FTC follicular thyroid carcinoma, FVPTC follicular
variant of papillary thyroid carcinoma, MTC medullary thyroid carcinoma, PTC papillary thyroid carcinoma)
Authors Year Study Journal Title Sample Age Single or Type of thyroid
Title size multiple carcinoma
toxic
nodules
Abs, R., et al. 1991 Hyperfunctioning Cancer 1 66 TMNG FTC (metastatic)
metastatic follicular
thyroid-carcinoma in
Pendreds syndrome
Alaoui, N. I. 2011 Association of Medecine Nucleaire- 7 41.4 4 Graves’ 5 PTC, 2 FTC
and N. Ben Rais hyperthyroidism and Imagerie disease, 2
well-differentiated Fonctionnelle single
thyroid carcinoma Et Metabolique AFTN, 1
(medullary excluded). TMNG
A propos of seven
cases.
Appetecchia, M. 1998 Hyperfunctioning Journal of Endocrinological 1 AFTN PTC
and M. Ducci [41] differentiated thyroid Investigation
carcinoma.
Ardito, G., 1997 Papillary thyroid European Journal of 1 AFTN PTC
et al. [42] carcinoma mimicking Surgical Oncology
an autonomous
functioning nodule.
Bajja, M. Y., 2017 Mucinous carcinoma Annales D Endocrinologie 1 74 AFTN Mucinous
et al. [43] of the thyroid: A case carcinoma of the
report and review of thyroid
the literature.
Barrande, 1997 Two thyroid carcinomas Presse Medicale 2 35 and AFTN
G., et al. mimicking toxic 55
adenomas.
Becker, F. O., 1963 The occurrence of Annals of Internal 2
et al. carcinoma in “hot” Medicine
thyroid nodules.
Report of two cases.
Bircan, R., et al. 2007 The second follicular Hormone Research 1 FTC
thyroid carcinoma
presenting as a hot
thyroid nodule with
a somatic 1486F TSH-
Receptor (TSHR) gene
mutation.
Bitterman, A., 2006 Thyroid carcinoma Otolaryngology - Head 1 66, 57, AFTN & PTC & 2 FTC
et al. [44] presenting as a hot & Neck Surgery 59 TMNG
nodule.
Bommireddipalli, 2010 Follicular variant of Clinical Nuclear Medicine 1 63 AFTN FVPTC
S., et al. [45] papillary thyroid carcinoma
presenting
as a toxic nodule by
I-123 scintigraphy.
Bourasseau, I., 2000 No evidence of Thyroid 4 Mean 3 AFTN, 1 2 PTC and 2 FTC
et al. thyrotropin receptor age 41.1 TMNG
and G(s alpha) gene
mutation in high iodine
uptake thyroid
carcinoma.
Calimon, M. A. P. 2014 Papillary Thyroid Endocrine Reviews 1 AFTN PTC
and S. W. Carcinoma in an
Lim-Uy [46] Autonomous
Hyperfunctioning
Thyroid Nodule.
Camacho, P., 2000 A Phe 486 thyrotropin Thyroid 1 49 AFTN FTC
Lau et al. Thyroid Research (2021) 14:3 Page 10 of 16

Table 4 Summary of 62 case reports identified through our search strategy that reported thyroid carcinomas within hot nodules.
(AFTN autonomously functioning thyroid nodules, TMNG toxic multinodular goiter, FTC follicular thyroid carcinoma, FVPTC follicular
variant of papillary thyroid carcinoma, MTC medullary thyroid carcinoma, PTC papillary thyroid carcinoma) (Continued)
Authors Year Study Journal Title Sample Age Single or Type of thyroid
Title size multiple carcinoma
toxic
nodules
et al. [47] receptor mutation in
an autonomously
functioning follicular
carcinoma that was
causing hyperthyroidism.
Campenni, A., 2011 Follicular variant of European Journal of 1 15 AFTN PTC
et al. [32] papillary thyroid Nuclear Medicine and
carcinoma presenting Molecular Imaging
as a toxic nodule in an
adolescent girl
Castelli, V., et al. 1994 Occurrence of papillary Thyroidology 1 PTC
carcinoma in a
hyperfunctioning thyroid
nodule: report of a case
and diagnostic
considerations
Cirillo, R. L., Jr., 1998 Metastatic pure papillary Clinical Nuclear Medicine 1 AFTN PTC (metastatic)
et al. [48] thyroid carcinoma
presenting as a toxic
hot nodule.
Clement, K., 1991 Thyroid cancer revealed Presse Medicale 1 62
et al. [49] by an extinctive hot
nodule
Damle, N., 2011 Papillary carcinoma Journal of Pediatric 2 6 AFTN PTC
et al. [33] masquerading as clinically Endocrinology & Metabolism months
toxic adenoma in very and 5y
young children.
De Rosa, G., 1990 Thyroid carcinoma European Journal of AFTN
et al. [50] mimicking a toxic Nuclear Medicine
adenoma.
Ducci, M., 1996 Differentiated carcinoma Acta otorhinolaryngologica 1 13 AFTN PTC
et al. [34] in autonomously functioning Italica: organo ufficiale della
thyroid nodule: case report. Società italiana di otorinolaringologia
e chirurgia cervico-facciale
Einert, A., 1995 A combination of unifocal Radiologe 1 53 AFTN FTC
et al. [51] thyroid autonomy and
follicular carcinoma - A
case report
Emmrich, P., 2001 Unifocal autonomous Zentralblatt Fur Chirurgie 2 AFTN FTC and PTC
et al. [52] thyroid nodule and
carcinoma.
Foppiani, L., 2005 Heterogeneous malignancy Journal of Endocrinological 3 68, 38, 2 AFTN, 1 3 FTC
et al. [53] in toxic thyroid nodules Investigation & 62 TMNG
Fuhrer, D., 2003 Two somatic TSH receptor Endocrine-Related Cancer 1 59 TMNG FTC
et al. [54] mutations in a patient with
toxic metastasising follicular
thyroid carcinoma and non-
functional lung metastases.
Fujimoto, Y., et al. 1972 Occurrence of papillary Endocrinologia Japonica 1
carcinoma in hyperfunctioning
thyroid nodule. Report of a
case.
Fukata, S., 1987 Thyroid carcinoma and hot European Journal of 1 70 AFTN PTC
et al. [55] nodule Nuclear Medicine
Gardner, D. and 2014 A rare cause of hyperthyroidism: BMJ Case Reports 1 66 TMNG FVPTC
Lau et al. Thyroid Research (2021) 14:3 Page 11 of 16

Table 4 Summary of 62 case reports identified through our search strategy that reported thyroid carcinomas within hot nodules.
(AFTN autonomously functioning thyroid nodules, TMNG toxic multinodular goiter, FTC follicular thyroid carcinoma, FVPTC follicular
variant of papillary thyroid carcinoma, MTC medullary thyroid carcinoma, PTC papillary thyroid carcinoma) (Continued)
Authors Year Study Journal Title Sample Age Single or Type of thyroid
Title size multiple carcinoma
toxic
nodules
S. C. Ho functioning thyroid metastases
Gozu, H. 2004 Does a Leu 512 Arg thyrotropin Thyroid 1 ? TMNG PTC
et al. [67] receptor mutation cause an
autonomously functioning
papillary carcinoma?
Kim, T. S., et al. 2007 A rare case of hyperfunctioning Acta Oto-Laryngologica 1 32 AFTN FVPTC
papillary carcinoma of the
thyroid gland
Kuan, Y. C. 2014 Thyroid papillary carcinoma Qjm 1 60 AFTN FVPTC
and F. H. Tan in a ‘hot’ thyroid nodule.
Lado-Abeal J. 2010 Identification of a paired Endocrine-Related Cancer 1 55 TMNG FTC
et al [68] box gene 8-peroxisome
proliferator-activated receptor
gamma (PAX8-PPAR gamma)
rearrangement mosaicism in
a patient with an autonomous
functioning follicular thyroid
carcinoma bearing an activating
mutation in the TSH receptor
Lima, M. J., et al. 2018 Autonomously hyperfunctioning International Journal of 1 49 AFTN FVPTC
cystic nodule harbouring Surgery Case Reports
thyroid carcinoma - Case report
and literature review.”
Majima, T., 2005 Papillary thyroid carcinoma Endocrine Journal 1 59 AFTN PTC
et al. [56] without metastases manifesting
as an autonomously functioning
thyroid nodule.
Marcelino, M., 2014 Anaplastic carcinoma and European Thyroid Journal 1 70 TMNG Anaplastic
et al. [28] toxic multinodular goiter: an thyroid
unusual presentation carcinoma
Mircescu, H., 2000 Hyperfunctioning malignant Journal of Pediatrics 1 11 AFTN PTC
et al. [35] thyroid nodule in an
11-year-old girl: pathologic
and molecular studies.
Mirfakhraee, 2013 A solitary hyperfunctioning Thyroid research 1 29 AFTN FTC
S., et al. [8] thyroid nodule harboring
thyroid carcinoma: review
of the literature
Nagai, G. R., et al. 1987 Scintigraphic hot nodules Clinical Nuclear Medicine 3 2 FTC and 1 PTC
and thyroid carcinoma
Nemec, J., 1980 Metastatic thyroid cancer Endokrinologie 1 AFTN FTC (metastatic)
et al. [57] with severe hyperthyroidism
mimicking independent
hyperfunctioning thyroid
adenoma, showing transition
to water-clear-tumour.
Niepomniszcze, 2006 Follicular carcinoma Thyroid 1 64 AFTN FTC
H., et al. [58] presenting as autonomous
functioning thyroid nodule
and containing an activating
mutation of the TSH receptor
(T620I) and a mutation of
the Ki-RAS (G12C) genes.
Nishida, A. T., 2008 Multifocal hyperfunctioning Auris, Nasus, Larynx 1 62 TMNG PTC
et al. [59] thyroid carcinoma without
metastases.
Lau et al. Thyroid Research (2021) 14:3 Page 12 of 16

Table 4 Summary of 62 case reports identified through our search strategy that reported thyroid carcinomas within hot nodules.
(AFTN autonomously functioning thyroid nodules, TMNG toxic multinodular goiter, FTC follicular thyroid carcinoma, FVPTC follicular
variant of papillary thyroid carcinoma, MTC medullary thyroid carcinoma, PTC papillary thyroid carcinoma) (Continued)
Authors Year Study Journal Title Sample Age Single or Type of thyroid
Title size multiple carcinoma
toxic
nodules
Polyzos, S. A. and 2011 Coincidental thyroid papillary Archives of Iranian Medicine 1 AFTN PTC
D. G. Goulis [30] microcarcinoma in a patient (microcarcinoma)
treated for a toxic adenoma
of the thyroid.
Rees, D. O., 2015 Follicular variant of papillary BMJ Case Reports 1 16 AFTN FVPTC
et al. [36] thyroid carcinoma: an unusual
cause of thyrotoxicosis.
Rivas, I., et al. [29] 1995 Medullary thyroid carcinoma Journal of 1 42 AFTN MTC
mimicking an autonomous Endocrinological
functioning nodule Investigation
Rubenfeld, S. and 1988 Thyroid cancer presenting Thyroidology 1 AFTN
T. M. Wheeler as a hot thyroid nodule:
report of a case and review
of the literature
Ruggeri, R. M., 2013 Follicular variant of papillary Thyroid 1 15 AFTN FVPTC
et al. [37] thyroid carcinoma presenting
as toxic nodule in an adolescent:
coexistent polymorphism of
the TSHR and Gsalpha genes.
Russo, D. 1997 Detection of an activating JCEM 1 60 AFTN Insular
et al. [70] mutation of the thyrotropin carcinoma
receptor in a case of an
autonomously hyperfunctioning
thyroid insular carcinoma
Russo, D. 1999 A Val 677 activating mutation Thyroid 1 42 AFTN Hurthle cell
et al. [69] of the thyrotropin receptor carcinoma
in a Hurthle cell thyroid
carcinoma associated with
thyrotoxicosis
Sablayrolles, 1983 Thyroid carcinoma Archives Francaises 1
B., et al. presenting as a hot nodule De Pediatrie
in a child
Salih, A. M., et al. 2016 Hyperfunctioning papillary nternational Journal 1 40 TMNG PTC
thyroid carcinoma: A case of Surgery Case Reports
report with literature review.
Sandler, M. P., 1988 Thyroid carcinoma Clinical Nuclear Medicine 1 AFTN PTC
et al. [60] masquerading as a solitary
benign hyperfunctioning
nodule
Sato, Y., et al. 1998 Hyperfunctioning thyroid Endocrine Journal 1 67 TMNG PTC
adenoma concomitant with
papillary thyroid carcinoma,
follicular thyroid adenoma
and primary hyperparathyroidism.
Schmidt, S., et al. 2016 Hyperfunctioning thyroid Langenbeck’s Archives 1 72 TMNG PTC
nodules (toxic adenoma)- of Surgery
underestimated risk of
malignancy?
Schneider, P. W., 2000 A clear cell variant of Thyroid 1 AFTN FTC
et al. [61] follicular carcinoma
presenting as an
autonomously functioning
thyroid nodule.
Sevinc, B., et al. 2018 Papillary thyroid carcinoma Marmara Medical Journal 1 55 AFTN PTC
after radioactive iodine
treatment for toxic thyroid
Lau et al. Thyroid Research (2021) 14:3 Page 13 of 16

Table 4 Summary of 62 case reports identified through our search strategy that reported thyroid carcinomas within hot nodules.
(AFTN autonomously functioning thyroid nodules, TMNG toxic multinodular goiter, FTC follicular thyroid carcinoma, FVPTC follicular
variant of papillary thyroid carcinoma, MTC medullary thyroid carcinoma, PTC papillary thyroid carcinoma) (Continued)
Authors Year Study Journal Title Sample Age Single or Type of thyroid
Title size multiple carcinoma
toxic
nodules
nodule: Case report.
Siddiqui, A. R. 1995 Hurthle cell-carcinoma in Pediatric Radiology 1 16 AFTN Hurthle cell
and S. an autonomous thyroid carcinoma
Karanauskas [38] nodule in an adolescent
Simsek, E., et al. 2014 Metastatic Papillary Endocrine Reviews 1 AFTN PTC (metastatic)
Thyroid Carcinoma in an
Autonomous Hyperfunctioning
Thyroid Nodule in an Adolescent
Sobel, R. J., et al. 1985 Papillary carcinoma and the Israel Journal of 3 AFTN PTC
solitary autonomously Medical Sciences
functioning nodule of
the thyroid.
Stahl, A., 2002 Differentiated thyroid Wiener Klinische 1 57 AFTN Metastatic
et al. [62] carcinoma in a scintigraphically Wochenschrift differentiated
hot nodule: diagnosis and thyroid
interdisciplinary therapeutical carcinoma
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Tangari, A., 2011 Hot nodule harboring a Hormone Research 1 3 AFTN PTC
et al. [31] papillary microcarcinoma in a in Paediatrics (microcarcinoma)
girl from an iodine sufficient
area.
Tfayli, H. M., 2010 Papillary thyroid carcinoma Thyroid 1 11 AFTN PTC
et al. [39] in an autonomous
hyperfunctioning thyroid
nodule: case report and
review of the literature
Uludag, M., et al. 2008 Autonomously functioning Hormones 1 36 AFTN PTC (columnar
thyroid nodule treated with type)
radioactive iodine and later
diagnosed as papillary
thyroid cancer.
Wong, C. P., 2003 Thyrotoxicosis: a rare Clinical Nuclear 1 AFTN Hurthle cell
et al. [63] presenting symptom of Medicine carcinoma
Hurthle cell carcinoma of
the thyroid.

inclusion of only patients undergoing partial or total thy- Summary

roidectomy. Given that these patients were selected for Current guidelines for the differential diagnosis and
thyroidectomy instead of treatment with antithyroid treatment of thyroid nodules recommend clinical assess-
medication or radioactive iodine therapy, there exists the ment and measurement of serum TSH levels [5, 78]. In
potential for a selection bias influencing our primary patients with low TSH levels, the next recommendation
outcome of the true rate of malignancy in hot nodules. involves thyroid scintigraphy with further malignancy
For example, in the cohort of patients selected for thy- risk stratification applied only to non-toxic nodules. The
roidectomy, as opposed to monitoring or radioactive AACE/AME guideline recognise that in geographic re-
iodine therapy, one reason for surgical intervention gions with past or present iodine deficiency scintigraphy
could be a high-risk sonographic pattern in the index is used as part of the evaluation of patients with MNG
hot nodule or other concurrent non-index lesions. In and that TSH may remain unsuppressed even when au-
this cohort, it would be logical to see a higher rate of tonomy is present [4].
malignancy than expected. Furthermore, rate of malig- Based on this systematic review, we were unable to
nancy may also vary based on geographical location, and identify a prospective study that directly compared
local clinical practices (predominance of surgical resec- the malignancy risk of hot nodules with non-toxic
tion versus treatment with radioactive iodine). nodules in adults. Also, each included study contained
Lau et al. Thyroid Research (2021) 14:3 Page 14 of 16

one or more limitations that negatively impacted its Abbreviations

ability to answer our primary question (see Table 1). TMNG: Toxic multinodular goiters; TSH: Thyrotropin/Thyroid-stimulating
hormone; PRISMA: Preferred reporting items for systematic review and meta-
The lack of a well conducted prospective study asses- analyses; FNAB: Fine needle aspiration biopsy; NTN: Non-toxic nodules;
sing the malignancy risk in all patients with hot nod- MNG: Multinodular goiters; PTC: Papillary thyroid carcinomas; fvPTC: Follicular
ules, together with the identification of 62 case variant of papillary thyroid carcinomas; ATA: American Thyroid Association;
AACE/ACE/AME: Amercian Association of Clinical Endocrinologist (AACE),
reports identifying thyroid carcinomas within hot American College of Endocrinology (ACE) and Associazione Medici
nodules, challenges the hypothesis that hot nodules Endocrinologi (AME)
are rarely malignant.
Acknowledgements
With limitations in mind, this systematic review Not applicable.
demonstrates that the odds of malignancy in hot nod-
ules are reduced by 49–62% compared to non-toxic Authors’ contributions
LWL and RP conceived and designed the study. HLR performed the search.
nodules. However, the overall rate of malignancy ob- LWL and AS performed the data extraction. ADF performed the data analysis.
served in hot nodules is higher than expected. Trad- LWL wrote the initial manuscript. LWL, SG, ADF, AS, HLR, DMR, and RP all
itionally, hot thyroid nodules were thought to rarely participated in the critical revision of the manuscript and contributed to the
final version. The author(s) read and approved the final manuscript.
harbour malignancy with rates reported as low as
0.34% [14]. Higher incidence of malignancy in hot Funding
nodules was observed in the seven included studies No funding sources were utilized.
ranging from 10 to 34% (Table 1) [9, 23–26]. FNA bi-
Availability of data and materials
opsy results available for 4 studies demonstrate a low All data generated or analysed during this study are included in this
diagnostic yield of FNA cytology for the diagnosis of published article and its supplementary information files.
malignancy (Table 2). A large number of studies were
Ethics approval and consent to participate
excluded from analysis for the inclusion of only hot Not applicable.
nodules without a comparison with non-toxic nodules
(Supplemental Table 3) [7, 10, 13–15, 65, 72, 79–98]. Consent for publication
Not applicable.
Furthermore, the search strategy identified 62 case re-
ports that described the presence of thyroid malig- Competing interests
nancy within a hot nodule (Table 4). The authors declare that they have no competing interests.
In summary, this systematic review highlights the
Author details
need for further research into the malignancy risk as- 1
Department of Medicine, Cumming School of Medicine, University of
sessment of hot nodules. There is sufficient evidence Calgary, Calgary, Canada. 2Section of Endocrinology and Metabolism,
Department of Medicine, Cumming School of Medicine, University of
to question the notion that hot nodules rarely
Calgary, Calgary, Canada. 3Arnie Charbonneau Cancer Institute, Cumming
harbour thyroid cancer. To adequately address this School of Medicine, University of Calgary, Calgary, AB, Canada. 4Clinical
question, a study of adult patients would need to in- Medicine. Health Sciences Library, University of Calgary, Calgary, Canada.
5
Department of Community Health Sciences, Cumming School of Medicine,
corporate both scintigraphically hot and non-toxic
University of Calgary, Calgary, AB, Canada. 6Departments of Oncology,
nodules, resected for any indication, with histologic Pathology, and Laboratory Medicine, Biochemistry and Molecular Biology,
correlation of the location of the nodule by pre- Cumming School of Medicine, University of Calgary, Calgary, Canada.
operative imaging (ultrasound and scintigraphy) and
Received: 10 September 2020 Accepted: 1 February 2021
histologic examination, and exclusion of low-risk pap-
illary microcarcinomas. Furthermore, if hot nodules
were to be subjected to further assessment, the ultra- References
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