Keywords
Hashimoto's thyroiditis - papillary thyroid cancer - multinodular goiter - thyroid
Hashimoto's thyroiditis (HT) was first described by Hakaru Hashimoto, a Japanese surgeon
and pathologist in 1912. It is the most common autoimmune thyroid disease and the
commonest cause of hypothyroidism.[1] The disease occurs in 0.3 to 1.5 per 1,000 individuals worldwide and is found to
be more common in females with gender preponderance of 5 to 20 times.[2] The pathophysiological hallmark of HT is diffuse lymphocyte infiltration of thyroid
follicles resulting in glandular destruction, fibrosis, and parenchymal atrophy, subsequently
causing thyroid dysfunction and occasional development of goiter.[3] Though 90% of patients with HT have high antithyroid peroxidase and antithyroglobulin
antibody titers, histological diagnosis is considered more accurate.[4] Sonographic findings of diffuse HT include decreased echogenicity, heterogenecity,
hypervascularity, and presence of hypoechoic micronodules with an echogenic rim.[5]
In the past, thyroiditis was considered as an uncommon disease incidentally diagnosed
by the presence of lymphocytic infiltration in thyroid follicles on histopathology
examination. Recently, increased number of thyroiditis has been reported. This could
parallel the steady rise in frequency of other autoimmune disorders, mostly in the
West and North of the world as compared with the East and South, probably due to modified
environmental triggers.[6]
[7]
[8] Thyroiditis has been associated with other autoimmune diseases like Type 1 diabetes
mellitus, multiple sclerosis, rheumatoid arthritis, celiac disease, vitiligo, and
chronic urticaria.[8]
[9]
[10]
[11] The association of HT with thyroid cancer, in particular papillary thyroid carcinoma
(PTC), was first described by Dailey et al in 1955.[12] This report underlined a significantly high prevalence of thyroid cancer in HT compared
with the general population. Although several publications did support these findings,[13]
[14] the investigations by Crile[15] in population-based studies of patients with HT challenged this association. Another
similar study done by Holm et al[16] in 829 patients added strong support to Crile's[16] findings. Later, Jankovic et al[4] did a systematic literature review in 2013 and concluded that population-based fine
needle aspiration studies did not find a statistically significant correlation between
HT and PTC. The objective of this study is to find out the prevalence of histopathologically
proven HT among patients who underwent thyroidectomy for various indications in our
institution and the association of HT with other thyroid diseases, especially thyroid
malignancies.
Materials and Methods
All patients aged 12 years or above, who underwent thyroidectomy for various indications
from 2011 to 2015 in the Department of General Surgery, in Government Medical College,
Trivandrum, Kerala, India, were included in this retrospective study. The main indications
for thyroidectomy were benign thyroid disease with pressure symptoms or cosmetic purposes;
suspicious nodule(s) in the thyroid by clinical examination, imaging, or fine needle
aspiration cytology (FNAC); and proven thyroid malignancy. All patients had undergone
FNAC before surgery except in thyrotoxicosis. Those patients who underwent isthmusectomy
alone for relieving pressure symptoms and thyroidectomy for underlying parathyroid
disease were excluded. HT was defined histologically by the presence of diffuse lymphocytic
infiltrates, lymphoid follicles with reactive germinal centers, Hurthle cell change
of the follicular epithelial cells, parenchymal atrophy, and fibrosis.
From the hospital registry, data were abstracted by the residents who were given adequate
training about the data abstraction protocol based on a pretested and standardized
data abstraction form. We had ascertained the feasibility and availability of information
needed for the data abstraction form by a preliminary review of three randomly selected
sample case records. We abstracted relevant data of all thyroidectomy cases from 2011
to 2015. Descriptive statistics are reported in mean and standard deviation or median
and interquartile range for continuous variables, and in absolute numbers and percentages
for categorical variables. Chi-square test with appropriate correction, if needed,
was used to find out the association between variables considered under the objective.
All statistical analyses were implemented in R statistical software version 3.2.0.
The level of significance was set at a p-value of 0.05.
Results
Total 4,631 patients who underwent thyroidectomy in our department for both benign
and malignant diseases of the thyroid during the study period and met the criteria
for inclusion were considered for analysis. Among this, histopathology report of one
patient could not be traced and hence excluded. Age of the patients while undergoing
thyroidectomy ranged from 12 to 82 years and the median age was 42 (34.51) years.
Among those, 60 patients were below the age of 18 years. In these 60 patients, the
indications included abnormal cytology, pressure effects, and cosmesis also. None
of these 60 patients were found to suffer from any familial thyroid disorders. Postoperative
histology revealed papillary cancer as the predominant finding in these patients,
22 (36.7%), followed by benign multinodular goiter (MNG), 15 (25%), lymphocytic thyroiditis,
15 (25%), cellular nodule, 4 (6.7%), and papillary cancer in a background of MNG,
4 (6.7%). The preoperative cytology results are displayed in [Table 1].
Table 1
Cytology distribution of all study patients
|
Multinodular goiter (MNG)
|
70.8%
|
|
Lymphocytic thyroiditis
|
9.8%
|
|
Papillary carcinoma
|
7.4%
|
|
Nondiagnostic
|
5%
|
|
Follicular neoplasm
|
4.6%
|
|
MNG with thyroiditis
|
3.2%
|
|
Papillary carcinoma with thyroiditis
|
0.7%
|
|
Hurthle cell neoplasm
|
0.5%
|
|
Normal thyroid cells
|
0.27%
|
|
Medullary carcinoma
|
0.2%
|
Most of them were female 4,075 (88%) with a female-to-male ratio of 7:1. The mean
age of the patients who presented with thyroiditis was 41.2 ± 11.8 years, whereas
in patients without thyroiditis, the age was 43.3 ± 12.2 years. Even though thyroiditis
and nonthyroiditis patients showed female predominance, it was more so with thyroiditis
patients. Among thyroiditis patients, females constituted 93.3% (female-to-male ratio,
14:1), and in nonthyroiditis patients, females constituted 85.9% (female-to-male ratio,
6:1). Out of the 4,630 thyroidectomies, 508 had undergone hemithyroidectomy, 29 had
subtotal thyroidectomy, 87 had near-total thyroidectomy, and 4,006 had total thyroidectomy.
So, the most frequent thyroid surgery performed was total thyroidectomy (86.5%).
In this study of 4,630 patients, histopathologically proven features of HT were present
in 1,295 (28%) patients, of which 445 (34.36%) had only HT while 850 (65.64%) had
HT along with other thyroid diseases. These 445 patients underwent surgery because
of pressure effects. The frequency distribution of thyroiditis in thyroidectomy specimens
is given in [Fig. 1]. The most common disease associated with HT was MNG (44.2%), followed by PTC (15.2%),
while 1.5% patients had both MNG and PTC. Other diseases in the decreasing order of
frequency were cellular nodule, follicular carcinoma, follicular adenoma, medullary
carcinoma, other malignancy, and Hurthle cell carcinoma. Altogether, HT coexists with
PTC in 216 (16.7%) cases, with other malignancies in 18 (1.38%) cases, and with other
benign thyroid diseases in 616 (47.6%) cases ([Table 2]). Moreover, patients with HT exhibited a higher rate of PTC compared with patients
without HT, irrespective of their gender (16.7% vs 13.8%, p = 0.013). Association between thyroiditis and papillary thyroid cancer is depicted
in [Fig. 2]. Male patients who underwent thyroidectomy harbored PTC more often than females
irrespective of their thyroiditis status. When 23% of male HT patients and 20.2% of
males without HT suffered from PTC, only 16.2% and 12.8% of females in the HT and
without HT group, respectively, had PTC. Statistically significant association exists
between PTC and thyroiditis in female patients (p = 0.003) whereas it is lacking in males (p = 0.56). The occurrence of PTC in HT patients and without HT patients with respect
to gender is given in [Table 3].
Fig. 1 Bar graph showing the distribution of thyroiditis in histopathology.
Table 2
Hashimoto's thyroiditis' coexistence with other thyroid pathologies
|
Thyroid disorder
|
Number (%)
|
|
Multinodular goiter (MNG)
|
573 (44.2)
|
|
Hashimoto's thyroiditis only
|
445 (34.4)
|
|
Papillary carcinoma
|
197 (15.2)
|
|
Cellular nodule
|
32 (2.47)
|
|
MNG with papillary carcinoma
|
19 (1.47)
|
|
Follicular carcinoma
|
11 (0.85)
|
|
Follicular adenoma
|
11 (0.85)
|
|
Medullary carcinoma
|
4 (0.31)
|
|
Hodgkin's lymphoma
|
1 (0.08)
|
|
Hurthle cell carcinoma
|
1 (0.08)
|
|
Secondary from unknown primary
|
1 (0.08)
|
|
Total
|
1,295 (100)
|
Fig. 2 Grouped bar graph showing association between thyroiditis and papillary thyroid cancer.
Table 3
Papillary cancer co-occurrence in patients with and without Hashimoto's thyroiditis
|
Sex
|
Thyroiditis present (n = 1,295)
|
Thyroiditis absent (n = 3,395)
|
p-Value
|
|
Total no.
|
PTC (%)
|
Total no.
|
PTC (%)
|
|
|
Female
|
1,208
|
196 (16.2)
|
2,866
|
366 (12.8)
|
0.003*
|
|
Male
|
87
|
20 (23)
|
469
|
95 (20.2)
|
0.56
|
|
Total
|
1,295
|
216 (16.7)
|
3,335
|
461 (13.8)
|
|
Abbreviation: PTC, papillary thyroid carcinoma.
Discussion
Since the initial description by Dailey et al[12] in 1955, the association between HT and thyroid malignancy remains controversial,
some studies suggesting a positive correlation while others strongly contradicting
this. Some studies even postulate a cause and effect relationship between the two.
The inflammatory response seen in HT stimulates the malignant transformation of follicular
cells through reactive oxygen mediated DNA damage. The conflicting report seen in
the literature may be due to differences in study design, selection bias, and ethnic
and geographical variations. In this study, we attempted to find out the prevalence
of HT in thyroidectomy in the Indian population and whether there exists any relationship
between HT and PTC.
The prevalence of HT in this study was 28%; of this, 18.4% had HT along with other
thyroid diseases and 9.5% had only HT. A study done in Korea by Yoon et al[17] reported a prevalence of 28.7% HT among PTC patients. But similar studies done by
Repplinger et al[18] and Siriweera and Ratnatunga[19] in thyroidectomy patients showed prevalence of HT as 18% and 6.51%, respectively,
based on final pathology. We focused our study on the distribution of various other
thyroid disorders in the subgroup of patients with pathologically proven HT. Among
this, 65.64% had associated thyroid pathologies, either benign or malignant. Overall,
benign disease of the thyroid was more frequently associated with HT (47.6%) than
malignancy (18%) and among the malignancies, PTC formed an overwhelming majority.
Since the association between HT and PTC has been widely disputed in the literatures
and both these diseases are common in our setting, we further explored the relationship.
Out of the 1,295 patients with HT, 16.7% had coexistent PTC and it was 12 times more
common than other thyroid malignancy. This could also be because PTC is the commonest
type among all thyroid malignancies. If stratified by gender, females were more frequently
affected by thyroid cancer than males, with female-to-male ratio of 9.6:1. There is
a statistically significant association between PTC and thyroiditis in female patients
(p = 0.003) whereas it is lacking in male patients. This may be because of the small
sample size of male patients or due to the fact that males with thyroid nodules are
often advised thyroidectomy with a lower threshold.
Resende de Paiva et al[20] conducted a large systematic review and meta-analysis involving 64,628 subjects
to find out the association between HT and thyroid cancer. Among the HT patients,
most of the patients were women (78.7%). PTC was seen in 9.03%, follicular carcinoma
in 1.26%, medullary carcinoma in 1.62%, anaplastic carcinoma in 0.49%, and thyroid
lymphoma in 0.37%. He concluded that an association exists between HT and PTC as well
as HT and thyroid lymphoma, but no association was found between HT and other thyroid
malignancies. In all subtypes of thyroid cancer, females were more often affected
than males with ratios ranging from 1.5:1 to 4.8:1. These findings go well with our
study. Daniel Repplinger et al[18] found that PTC occurred in 29% of patients with HT and 23% of patients without HT.
Though PTC was the most common malignancy in patients with or without HT, it was significantly
less common in non-HT group (94% vs 76%, p = 0.001). A histopathology study assessing the prevalence and severity of thyroiditis
among surgically resected thyroid tumors found a significantly higher rate of lymphocytic
infiltrate in PTC.[21] Most of the thyroidectomy specimen studies reported a positive correlation between
HT and PTC.[3]
[22]
[23]
[24] However, FNAC studies done in the outpatient setting did not find a statistically
significant association between the presence of HT and PTC. For example, Matesa-Anić
et al[25] analyzed FNAC of 10,508 patients and found that the prevalence of PTC in patients
with HT was 1.9% and patients without HT was 2.7%. A similar observation was seen
in other FNAC studies.[16]
[26]
To date, the causative relationship between HT and PTC is not clearly established,
though there are some proposed mechanisms in the literature. Wirtschafter et al[27] and Arif et al[28] in two different studies demonstrated expression of the RET/PTC1 and RET/PTC3 oncogenes
in HT. Further study by Unger et al[29] found the expression of p63 in HT patients with PTC. Burstein et al[30] hypothesized that both HT and PTC are initiated by pluripotent p63-positive stem
cell remnants. Another hypothesis states that elevated levels of thyroid stimulating
hormone found in HT patients with hypothyroidism stimulate follicular epithelial proliferation,
leading to PTC.[15]
[31]
[32]
Our study was on a large series of patients who underwent thyroidectomy for various
indications mentioned above, over a span of 5 years. The limitation of this study
is that this is a hospital-based retrospective study comprising thyroidectomy patients
alone, hence subjected to selection bias. Also, we could not find complete information
about these patients, including their thyroid hormone status and thyroid antibodies
status.
But population-based studies in the literature with FNAC for diagnosing HT and coexistent
PTC have met with several problems. The presence of HT in a patient can be confirmed
only by histopathology examination of the entire gland. Focal HT and small PTC can
be missed by FNAC due to sampling error. Furthermore, follicular cell changes associated
with HT can be mistaken for thyroid neoplasm. In addition, several studies did not
have a control group. A prospective study in a community or outpatient setting with
clinical, imaging, antithyroid antibodies, and ultrasound-guided FNAC as a diagnostic
tool for HT would probably address this issue. In the future, a prospective histopathology
study of thyroid specimens obtained from a large number of subjects is required to
establish the association between HT and PTC conclusively.
Conclusion
The prevalence of HT in patients undergoing thyroidectomy is high in Kerala state
in India. Benign diseases of the thyroid are more frequently associated with HT than
malignancy. A statistically significant association exists between papillary cancer
and thyroiditis in female patients. We recommend that all patients with HT undergo
periodic thyroid evaluation to exclude the development of papillary cancer. We also
recommend further research to elucidate the association between thyroiditis and thyroid
malignancy.
