Thyroid Cancer in Surgically Treated Multinodular Goiter: Incidence and Histopatological Outcomes
Conditions: Goiter, Nodular, Total Thyroidectomy, Thyroid Cancer
Sponsor: University of Foggia

 
 
THYROID CANCER IN SURGICALLY TREATED 
MULTINODULAR GOITER: INCIDENCE AND 
HISTOPATHOLOGICAL OUTCOMES 
 
 
NCT NUMBER not available. 
 
 Date of document: 15/12/2023 
 
 
 
 

 
 
ABSTRACT 
INTRODUCTION 
Thyroid cancer, the most common endocrine malignancy, has been extensively studied due to its 
rising global incidence and diverse clinical presenta琀椀ons. Among thyroid disorders, mul琀椀nodular 
goiter (MNG) is frequently encountered in clinical prac琀椀ce, with a prevalence ranging from 0.4% to 
7.2% in iodine-su昀케cient regions and a昀昀ec琀椀ng approximately 25– 33% of the popula琀椀on in iodine-
de昀椀cient areas. 
The associa琀椀on between MNG and thyroid cancer is well-documented, although reported incidence 
rates vary signi昀椀cantly among studies and popula琀椀ons, ranging from 5% to 35% in the literature  
This study aims to inves琀椀gate, based on exis琀椀ng knowledge, the incidence of occult thyroid carcinoma 
in a cohort of pa琀椀ents with MNG, providing new insights into the prevalence and characteris琀椀cs of 
thyroid malignancies in MNG. It seeks to contribute to op琀椀mizing diagnos琀椀c evalua琀椀ons for pa琀椀ents 
with mul琀椀nodular goiter.  
 
MATHERIALS AND  METHODS 
This retrospec琀椀ve study included pa琀椀ents with a preopera琀椀ve diagnosis of mul琀椀nodular goiter who 
underwent total or par琀椀al thyroidectomy from January 2018 to May 2024 at the Department of 
Medical and Surgical Sciences at the University Hospital <Ospedali Riuni琀椀= in Foggia. The study's 
objec琀椀ve was to inves琀椀gate the incidence of thyroid carcinoma in pa琀椀ents undergoing thyroidectomy 
for MNG, also analyzing associated demographic and clinical variables.  
 
RESULTS 
Out of the 223 pa琀椀ents, 32 cases of thyroid carcinoma were diagnosed, corresponding to an incidence 
rate of 14.4% . Among these, 24 were female (75%) and 8 were male (25%), with a female-to-male 

 
ra琀椀o of 3:1. Thyroid carcinoma was iden琀椀昀椀ed in 13.3% of all females and 19% of all males. Although 
a di昀昀erence in incidence between the sexes was observed, it was not sta琀椀s琀椀cally signi昀椀cant 
(chi=0.929; p=0.335).  
Papillary thyroid carcinoma (PTC) was the most common type, iden琀椀昀椀ed in 25 cases (78.1%).  
The mean age of pa琀椀ents with thyroid carcinoma was 49.4 years (SD 16.7), with an age range of 22 
to 72 years. A signi昀椀cant di昀昀erence was observed between this group and the mean age of pa琀椀ents 
without carcinoma (mean: 56.2 years, SD 13.1). Sta琀椀s琀椀cal analysis indicated a signi昀椀cant di昀昀erence 
between the two groups in terms of age (t=-2.686; p=0.008). Addi琀椀onally, evalua琀椀ng the correla琀椀on 
between age and malignancy revealed that for each addi琀椀onal year of age, the probability of 
carcinoma decreased by 3.7% (OR=0.963; p=0.009).  
 
CONCLUSION 
The results of this study highlight a signi昀椀cant incidence of thyroid carcinoma in pa琀椀ents with 
mul琀椀nodular goiter. The predominant histotype was papillary carcinoma, with no observed sex-based 
di昀昀erences in incidence. The iden琀椀昀椀ed risk factors, such as age and thyroid weight, while poten琀椀ally 
useful for stra琀椀fying risk in pa琀椀ents with mul琀椀nodular goiter, are insu昀케cient—due to study limita琀椀ons 
and the signi昀椀cant variability among popula琀椀ons from di昀昀erent regions—to jus琀椀fy modi昀椀ca琀椀ons to 
exis琀椀ng thyroid nodule screening criteria.  
 
 
 
 
 
 
 

 
 
Keywords: mul琀椀nodular goiter; incidental thyroid cancer; total thyroidectomy; endocrine surgery 
Introduc琀椀on  
Thyroid cancer, the most common endocrine malignancy, has been extensively studied due to its 
rising global incidence and diverse clinical presenta琀椀ons. Among thyroid disorders, mul琀椀nodular 
goiter (MNG) is frequently encountered in clinical prac琀椀ce, with a prevalence ranging from 0.4% to 
7.2% in iodine-su昀케cient regions and a昀昀ec琀椀ng approximately 25– 33% of the popula琀椀on in iodine-
de昀椀cient areas. [1] It is characterized by an enlarged thyroid gland containing mul琀椀ple nodules. The 
pathogenesis of MNG involves various gene琀椀c, environmental, and dietary factors leading to the 
development of mul琀椀ple thyroid nodules.  
The associa琀椀on between MNG and thyroid cancer is well-documented, although reported incidence 
rates vary signi昀椀cantly among studies and popula琀椀ons, ranging from 5% to 35% in the literature [2]. 
Bove et al. reported an overall incidence of 8.9% in 2023, including 6.1% microcarcinoma cases and 
2.8% thyroid carcinoma cases [3]. In 2021, a study involving 3,233 pa琀椀ents found thyroid carcinoma 
in 1,026 of them, corresponding to an incidence of 31.7% [4-5]. Another study conducted in Southern 
Italy, focusing on a gene琀椀cally homogeneous popula琀椀on in Calabria with mild to moderate iodine 
de昀椀ciency, reported an overall prevalence rate of incidental thyroid carcinoma of 12.5% [6].  
These di昀昀erences may par琀椀ally stem from gene琀椀c variability among popula琀椀ons and sociocultural 
factors, par琀椀cularly diet. However, the rela琀椀onship between iodine intake and thyroid cancer remains 
controversial. A昀琀er iodine intake increased due to salt iodiza琀椀on and iodine supplementa琀椀on, the 
incidence of thyroid cancer, par琀椀cularly papillary thyroid carcinoma (PTC), rose despite a decrease in 
follicular thyroid carcinoma (FTC) incidence. Conversely, some meta-analyses on the associa琀椀on 
between iodine intake and thyroid cancer have found that higher iodine intake correlates with a lower 
risk of thyroid cancer [7]. Other studies indicate an associa琀椀on between excessive body fat, obesity, 
and overweight status with thyroid neoplasia [8; 9]. These 昀椀ndings highlight the intricate rela琀椀onship 
between diet and thyroid pathology, emphasizing the need for op琀椀mal dietary strategies.  
Although most nodules in MNG are benign, the presence of mul琀椀ple nodules complicates the 
iden琀椀昀椀ca琀椀on of poten琀椀ally malignant ones. It has long been believed that the risk of cancer in MNG 
is much lower than in solitary nodules. However, recent literature indicates that if a nodule in MNG 

 
grows consistently, becomes markedly dominant, or changes in consistency, its risk of malignancy 
matches that of a solitary nodule. Fineneedle aspira琀椀on (FNA) can di昀昀eren琀椀ate thyroid nodules with 
a high risk of malignancy, warran琀椀ng surgical removal, from benign goitrous nodules manageable 
with pharmacological therapy. FNA is associated with falsenega琀椀ve rates of approximately 3% for 
solitary nodules [9]. However, the diagnos琀椀c process is complicated by the number of nodules and 
the need to select those for biopsy, which may reduce the sensi琀椀vity of the procedure [10-11]. The 
applica琀椀on of TIRADS ultrasound criteria can aid in iden琀椀fying suspicious nodules, guiding further 
diagnos琀椀c assessments.  
Advancements in molecular tes琀椀ng have also contributed to evalua琀椀ng thyroid nodules. Nikiforov et 
al. (2011) discussed the use of molecular markers such as BRAF, RAS muta琀椀ons, and RET/PTC 
rearrangements in predic琀椀ng thyroid cancer. Their study demonstrated that integra琀椀ng molecular 
tes琀椀ng with tradi琀椀onal diagnos琀椀c methods improves malignancy detec琀椀on accuracy in MNG [12]. 
Similarly, Agrawal et al. (2012) highlighted the poten琀椀al of molecular diagnos琀椀cs to re昀椀ne risk 
stra琀椀昀椀ca琀椀on and management of thyroid nodules [13].  
The associa琀椀on between gender and thyroid cancer has yielded con昀氀ic琀椀ng results. A recent study 
found that men had a higher risk of incidental papillary thyroid carcinoma [4], whereas others 
reported a higher prevalence of incidental thyroid carcinoma in the female popula琀椀on [3; 6].  
The collec琀椀ve 昀椀ndings from these studies underscore the complex and only par琀椀ally understood 
interac琀椀on between MNG and thyroid cancer. Although the incidence of malignancy within MNG is 
rela琀椀vely low, a rigorous diagnos琀椀c approach is essen琀椀al for the 琀椀mely and accurate iden琀椀昀椀ca琀椀on of 
tumors. Integra琀椀ng ultrasound imaging, FNA, and molecular tests has enhanced diagnos琀椀c precision, 
enabling more informed clinical decisions. Moreover, iden琀椀fying correla琀椀ons with demographic and 
clinical factors could help re昀椀ne risk stra琀椀昀椀ca琀椀on and pa琀椀ent management in MNG.  
This study aims to inves琀椀gate, based on exis琀椀ng knowledge, the incidence of occult thyroid carcinoma 
in a cohort of pa琀椀ents with MNG, providing new insights into the prevalence and characteris琀椀cs of 
thyroid malignancies in MNG. It seeks to contribute to op琀椀mizing diagnos琀椀c evalua琀椀ons for pa琀椀ents 
with mul琀椀nodular goiter.  
  
 
 

 
 
Materials and Methods  
  
Pa琀椀ents  
This retrospec琀椀ve study included pa琀椀ents with a preopera琀椀ve diagnosis of mul琀椀nodular goiter who 
underwent total or par琀椀al thyroidectomy from January 2018 to May 2024 at the Department of 
Medical and Surgical Sciences at the University Hospital <Ospedali Riuni琀椀= in Foggia. The study's 
objec琀椀ve was to inves琀椀gate the incidence of thyroid carcinoma in pa琀椀ents undergoing thyroidectomy 
for MNG, also analyzing associated demographic and clinical variables.  
Diagnoses of mul琀椀nodular goiter were con昀椀rmed through clinical and ultrasound examina琀椀ons. 
Tissue samples obtained during surgery were analyzed by expert pathologists to iden琀椀fy thyroid 
carcinoma.  
Inclusion criteria were: (1) pa琀椀ents diagnosed with mul琀椀nodular goiter via thyroid ultrasound, with 
or without FNA cytology, (2) pa琀椀ents who underwent surgery, and (3) availability of complete clinical 
data. Exclusion criteria were: pa琀椀ents with a history of thyroid carcinoma or other thyroid neoplasms, 
those who did not complete postopera琀椀ve follow up, and pa琀椀ents with preopera琀椀ve FNA results 
indica琀椀ng malignancy (TIR 4–5), suspicion of malignancy (TIR 3), or indeterminate signi昀椀cance (TIR 1) 
per the 2014 criteria of the Italian Society of Pathological Anatomy and Cytology (SIAPEC).  
Demographic, clinical, and pathological data were collected from paper and/or electronic medical 
records. These included age, sex, results of any FNA cytology, type of surgery, weight of the resected 
thyroid, and de昀椀ni琀椀ve histopathological 昀椀ndings.  
  
Sta琀椀s琀椀cal Analysis  
Con琀椀nuous variables were represented as mean values along with standard devia琀椀on (SD), while 
categorical variables were presented as counts and percentages. Percentages were compared using 
Pearson’s chi-square test, a sta琀椀s琀椀cal method employed to assess whether the observed frequency 
distribu琀椀on di昀昀ers signi昀椀cantly from the expected distribu琀椀on in a given sample. In essence, it 
evaluates whether two categorical variables are independent.  

 
To inves琀椀gate poten琀椀al correla琀椀ons between con琀椀nuous variables and the presence of malignancy, 
an independent samples Student’s t-test was conducted. This test determines whether there are 
sta琀椀s琀椀cally signi昀椀cant di昀昀erences between the means of two groups.  
Logis琀椀c regression analysis was performed to examine the poten琀椀al rela琀椀onship between age and 
incidental thyroid carcinoma (ITC). Logis琀椀c regression is a sta琀椀s琀椀cal test used to analyze the 
rela琀椀onship between a binary dependent variable (e.g., yes/no, 0/1) and one or more independent 
variables. This method es琀椀mates the impact of independent variables on the dependent variable. 
The resul琀椀ng odds ra琀椀os (OR) were reported with 95% con昀椀dence intervals (CI). A signi昀椀cance level 
of 0.05 was selected to determine sta琀椀s琀椀cal signi昀椀cance. Sta琀椀s琀椀cal analysis was conducted using SPSS 
so昀琀ware.  
  
  
  
Results  
  
Charateris琀椀cs  
  
Mean (SD) or Number (%) 
  
Male, no  
 
42 (18,8%) 
  
Female, no  
 
181 (81,2%) 
  
Age, years  
  
Benign FNA (TIR2), no  
 
55,3 (±13,5) 
 
151 (67,7%) 
  
FNA not done, no  
 
72 (32,3%) 

 
  
Total thyroidectomy, no 
 
202 (90,6%) 
  
Lobectomy, no  
  
Thyroid wheight, grams 
 
21 (9,4%) 
 
68,4 (±57,9) 
Table 1: carateris琀椀cs of the study partecipants  
  
The study included a cohort of 223 pa琀椀ents diagnosed with mul琀椀nodular goiter (MNG) at our center 
between January 2018 and May 2024. The cohort consisted of 181 females (81.2%) and 42 males 
(18.8%), with a mean age of 55.3 years (SD 15.5). All cases were benign mul琀椀nodular goiter, with 151 
pa琀椀ents (67.7%) undergoing 昀椀ne-needle aspira琀椀on (FNA) yielding benign results, and 72 pa琀椀ents 
(32.3%) not undergoing FNA. All pa琀椀ents underwent surgical treatment for symptoma琀椀c goiter 
(compressive symptoms, hypo-/hyperthyroidism), with 202 (90.6%) undergoing total thyroidectomy 
and 21 (9.4%) undergoing lobectomy (Table 1). Pa琀椀ents diagnosed with incidental carcinoma post-
total thyroidectomy were referred directly for endocrinological and oncological follow-up, while those 
who underwent lobectomy received the same guidance following comple琀椀on of thyroidectomy.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
Charateris琀椀cs 
  
  
Mean (SD) or Number (%) 
 Carcinoma, no  
 32 (14,4%) 
 M  
 8 (25%) 
F  
 24 (75%) 
Benigne neoplasms, no  
 
22 (10,9%) 
Age, years 
49,4 (±16,7) 
Benign FNA (TIR2), no 
18 (56,3%) 
FNA not done, no 
18 (56,3%) 
Total thyroidectomy, no  
29 (90,6%) 
Lobectomy, no 
3 (9,4%) 
Thyroide weight, grams 
50,9 (±48,1) 
Table 2: charateris琀椀cs of pa琀椀ent with carcinoma  
  
Out of the 223 pa琀椀ents, 32 cases of thyroid carcinoma were diagnosed, corresponding to an incidence 
rate of 14.4% (Table 2). Among these, 24 were female (75%) and 8 were male (25%), with a female-
to-male ra琀椀o of 3:1. Thyroid carcinoma was iden琀椀昀椀ed in 13.3% of all females and 19% of all males. 
Although a di昀昀erence in incidence between the sexes was observed, it was not sta琀椀s琀椀cally signi昀椀cant 
(chi=0.929; p=0.335).  
The diagnosis of carcinoma was con昀椀rmed through postopera琀椀ve histopathological examina琀椀on, 
which classi昀椀ed the subtypes of thyroid carcinoma present in the sample. Papillary thyroid carcinoma 
(PTC) was the most common type, iden琀椀昀椀ed in 25 cases (78.1%), including 16 cases (50%) of 
microcarcinoma (pT1a; <1 cm) and 9 cases of classic PTC. Follicular thyroid carcinoma was diagnosed 

 
in 5 cases (15.6%), while 1 case of anaplas琀椀c carcinoma and 1 case of Hurthle cell carcinoma were 
iden琀椀昀椀ed.  
No cases of medullary carcinoma were reported (Figure 1).  
 
  
Regarding benign neoplasms, 20 follicular adenomas, 1 Hurthle cell adenoma, and 1 NIFTP (non-
invasive follicular thyroid neoplasm with papillary-like nuclear features) were iden琀椀昀椀ed.  
The mean age of pa琀椀ents with thyroid carcinoma was 49.4 years (SD 16.7), with an age range of 22 
to 72 years. A signi昀椀cant di昀昀erence was observed between this group and the mean age of pa琀椀ents 
without carcinoma (mean: 56.2 years, SD 13.1; Figure 2). Sta琀椀s琀椀cal analysis indicated a signi昀椀cant 
di昀昀erence between the two groups in terms of age (t=-2.686; p=0.008). Addi琀椀onally, evalua琀椀ng the 
correla琀椀on between age and malignancy revealed that for each addi琀椀onal year of age, the probability 
of carcinoma decreased by 3.7% (OR=0.963; p=0.009).  
  
Figure 1 : s ubtypes o f   thyroid   ca rcinoma   
Papillary carcinoma 
Follicular carcinoma 
Anaplastic carcinoma 
Hurtle cell carcinoma 

 
 
Figure 2: age in the groups whit an without carcinoma  
  
No signi昀椀cant di昀昀erences were found between the mean ages of male and female pa琀椀ents with 
carcinoma.  
Following surgical removal, the weight of the thyroid glands was assessed as an indica琀椀ve parameter 
of size, volume, and the density of the thyroid parenchyma, serving as a characteris琀椀c that integrates 
mul琀椀ple structural factors of the organ a昀昀ected by MNG.  
 
Figure 3: weight in the groups with and without carcinoma  
  
44 
46 
48 
50 
52 
54 
56 
58 
NO 
SI 
CANCER 
WITH                                                                              WITHOUT 
  
00 
, 
0 
00 
, 
10 
20 00 
, 
00 
, 
30 
40 , 00 
00 
, 
50 
60 00 
, 
00 
, 
70 
00 
, 
80 
NO 
SI 
CANCER 
W IT H                                                                            
W IT H OUT   

 
The mean thyroid weight in pa琀椀ents with ITC was 50.9 grams (SD 48.1), compared to 71.3 grams (SD 
59.0) in pa琀椀ents without ITC (Figure 3). This di昀昀erence was sta琀椀s琀椀cally signi昀椀cant (t=-1.855; p=0.032). 
No signi昀椀cant di昀昀erences in carcinoma incidence were observed between pa琀椀ents with benign FNA 
results and those who did not undergo FNA.  
  
Discussion  
The observed incidence of 14.4% higlight a signi昀椀cant risk of thyroid carcinoma development in 
pa琀椀ents with MNG compared to the general popula琀椀on. This 昀椀nding aligns with recent studies 
conducted in various Italian popula琀椀ons [14, 15], including those by Bove et al. (2023), Spaziani et al. 
(2023), and Chiefari et al. (2024) [3, 16, 6]. However, unlike these studies, which reported a signi昀椀cant 
prevalence in females, and the study by Apostolou et al. (2021) [4], which showed an increased 
incidence in males, our data revealed no notable sex-based di昀昀erences in carcinoma distribu琀椀on. This 
昀椀nding deviates from exis琀椀ng literature.  
Although prevalence indices vary slightly, our 昀椀ndings regarding histotype distribu琀椀on con昀椀rm, in 
agreement with numerous other studies [2-6, 15], that papillary thyroid carcinoma is the most 
prevalent subtype among pa琀椀ents with MNG, followed by follicular thyroid carcinoma.  
It is noteworthy that Hurthle cell carcinoma, reported as such based on the 2018 histopathological 
classi昀椀ca琀椀on, is now de昀椀ned to as <oncocy琀椀c carcinoma= according to the 2022 WHO guidelines [18].  
Given that half of the cases were papillary microcarcinomas, it is essen琀椀al to emphasize their 
favorable prognosis despite their scien琀椀昀椀c interest. Although progression rates are below 15% over 
10 years, they tend to increase with younger age at diagnosis [18, 19]. Older pa琀椀ents are ideal 
candidates for ac琀椀ve surveillance with ultrasonographic monitoring, while younger pa琀椀ents may 
bene昀椀t more from surgery. However, most young pa琀椀ents would also qualify for ac琀椀ve surveillance, 
as surgery may not be required during their life琀椀me [20, 21].  
Regarding age as a risk factor for thyroid carcinoma in MNG pa琀椀ents, the literature reports con昀氀ic琀椀ng 
data. Some studies found no signi昀椀cant rela琀椀onship between age and malignancy [4, 22], whereas 
others, consistent with our 昀椀ndings, reported higher tumor prevalence in younger pa琀椀ents [23, 24].  
Benign neoplasms, of which 22 cases were iden琀椀昀椀ed, require only conserva琀椀ve surgical management 
without the need for radioac琀椀ve iodine therapy or ultrasonographic surveillance due to their low 
progression rates. Thyroid weight has been implicated as a poten琀椀al risk factor for ITC [4, 22, 

 
25,26,27]. Based on the exis琀椀ng literature [4, 22], clinical observa琀椀ons, and diagnos琀椀c pathways for 
malignancies in goitrous thyroids, we hypothesized that smaller thyroids with lower nodular density 
(cys琀椀c or spongiform appearance) are more prone to ITC, owing to diagnos琀椀c challenges with 
ultrasonography and FNA. This hypothesis was con昀椀rmed by our 昀椀ndings. Thyroid weight should 
therefore be considered a poten琀椀al risk factor in the clinical management of MNG pa琀椀ents to ensure 
early detec琀椀on of associated thyroid malignancies [28, 29]. 
The primary limita琀椀ons of this study include the small sample size, the fact that the pa琀椀ents were 
recruited from a single center, and their representa琀椀on of a gene琀椀cally homogeneous popula琀椀on. 
While the la琀琀er reduces poten琀椀al sta琀椀s琀椀cal errors related to gene琀椀c factors, it limits the 
generalizability of the 昀椀ndings.  
The di昀케culty in collec琀椀ng certain parameters due to incomplete data allowed for the evalua琀椀on of 
only a limited number of disease-related aspects, although these proved to be signi昀椀cant.  
 
  
Conclusion  
The results of this study highlight a signi昀椀cant incidence of thyroid carcinoma in pa琀椀ents with 
mul琀椀nodular goiter. The predominant histotype was papillary carcinoma, with no observed sex-based 
di昀昀erences in incidence. The iden琀椀昀椀ed risk factors, such as age and thyroid weight, while poten琀椀ally 
useful for stra琀椀fying risk in pa琀椀ents with mul琀椀nodular goiter, are insu昀케cient—due to study limita琀椀ons 
and the signi昀椀cant variability among popula琀椀ons from di昀昀erent regions—to jus琀椀fy modi昀椀ca琀椀ons to 
exis琀椀ng thyroid nodule screening criteria.  
These results are an excellent star琀椀ng point and instead underscore the need for mul琀椀center studies 
aimed at developing speci昀椀c monitoring protocols for this pa琀椀ent popula琀椀on. Such protocols could 
enable 琀椀mely and targeted interven琀椀ons, ul琀椀mately improving clinical outcomes and reducing 
morbidity associated with thyroid carcinoma.  
  
  
 

 
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