Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study

  • Authors:
    • Kai Wu
    • Liuhong Shi
    • Jianbiao Wang
    • Lei Xie
  • View Affiliations

  • Published online on: March 1, 2023     https://doi.org/10.3892/ol.2023.13734
  • Article Number: 148
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The aim of the present study was to evaluate the association between coexisting lymphocytic thyroiditis (LT) and the clinicopathological features of papillary thyroid carcinoma (PTC). The records of 458 patients with PTC who underwent a total thyroidectomy and lymph node dissection in Sir Run Run Shaw Hospital (Hangzhou, China) were analyzed. In accordance with the histopathology of thyroid parenchyma, the cases were divided into three groups, including Hashimoto's thyroiditis (HT), non‑Hashimoto's type LT (NHLT) and no LT. Based on the histopathology, data on age, sex, maximum diameter of tumor, multifocality, extrathyroidal extension, metastatic lymph node size, extranodal extension and tumor grades in the different groups were analyzed and compared. The prevalence of coexisting LT was 29.0% (133/458), of which 7.6% (35/458) was HT and 21.4% (98/458) was NHLT. PTC concomitant with LT was significantly associated with female patients (95.5 vs. 70.2%; P<0.001), a lower rate of extrathyroidal extension and/or capsular invasion (25.6 vs. 39.7%; P=0.004), central lymph node metastasis (CLNM) ratio (10.71 vs. 17.37; P=0.014), higher number of dissected central lymph nodes (16.83 vs. 11.7; P<0.001), larger metastatic lymph nodes (0.66 vs. 0.46 cm; P<0.001), higher occurrence of multifocality (61.7 vs. 50.5%; P=0.029) and earlier pT stage (57.9 vs. 38.8%; P<0.001), regardless of the combined or separate consideration of HT and NHLT. Besides, LT was associated with multifocality [odds ratio (OR), 1.578; 95% confidence interval (CI), 1.046‑2.382; P=0.030]. Furthermore, in patients with PTC, CLNM had a significant association with the male sex (OR, 2.000; 95% CI, 1.216‑3.288; P=0.006), an age of <45 years (OR, 0.592; 95% CI, 0.398‑0.879; P=0.009) and a tumor size of >1 cm (OR, 3.913; 95% CI, 2.431‑5.734; P<0.001). In conclusion, patients with PTC and LT showed a greater female preponderance, multifocality, a lower extrathyroidal extension and a lower CLNM ratio. LT was associated with an increased risk of multifocality in PTC.

Introduction

Papillary thyroid carcinoma (PTC) coexisting with Hashimoto's thyroiditis (HT) currently remains a research hotspot and is controversial. The coexistence was first reported by Dailey et al (1) in 1955, and a vast number of studies subsequently explored the epidemiology and etiology of the concurrent diseases (24). However, the precise pathogenesis of these diseases arouses a fierce argument.

A number of studies demonstrated that HT was significantly associated with the prevalence of PTC (2,3,5). Numerous studies also indicated that patients with PTC and HT were associated with a better prognostic outcome, such as a smaller tumor size and lower tumor grade. HT in patients with PTC was also associated with better locoregional control, a lower recurrence rate and a greater survival rate (6,7). As for this favorable prognosis, one hypothesis suggested that the immune response of lymphocytic infiltration in patients with PTC plays a vital role in controlling tumor growth and proliferation (8). Conversely, it was reported that the co-occurrence of HT and PTC showed no protection of patient outcome (5), while another study suggested that patients with PTC and lymphocytic thyroiditis (LT) were associated with multifocal involvement (7).

Numerous investigators have reported that clinicopathological features, such as tumor size, multifocality, capsular invasion and central lymph node metastasis (CLNM), are associated with the prognosis of PTC (5,9,10). Nevertheless, there are few published studies with regard to the association between coexisting HT and PTC tumor grades, bilaterality, multifocality and especially histological CLN characteristics (size, number and extranodal extension) using the histopathological results (2). To investigate whether the coexistence of LT or HT in patients with PTC may result in a better outcome, the present study was conducted to assess the prevalence of coexistent LT or HT in patients who received thyroid surgery for PTC in a retrospective cohort. The study also explored the association between LT or HT in patients with PTC and clinicopathological features. Furthermore, the study sought to investigate the potential risk factors of the prognosis of PTC, especially multifocality PTC (MPTC) with coexistent LT.

Materials and methods

Patients

A total of 458 patients with primary PTC who underwent initial total thyroidectomy surgery with therapeutic or prophylactic central lymph node dissection (LND) (398 patients) or lateral LND (60 patients) between January 2012 and December 2014 in Sir Run Run Shaw Hospital (Hangzhou, China) were included in the present study. This retrospective study was approved by the Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine (Hangzhou, China). All patients provided written informed consent before the study. The inclusion criteria were patients with primary PTC and a complete a medical history, excluding those with a previous thyroidectomy, and excluding incidental PTC during thyroid surgery for benign neoplasms (without neck dissection).

Examinations

All patients received a preoperative evaluation, including a physical examination, laboratory tests and an imaging examination. Initial assessment was conducted by routine physical examination and ultrasonography (US) of the thyroid and neck lymph nodes (central and lateral). After an abnormal finding and a suspected tumor on US, an US-guided fine-needle aspiration (FNA) was performed to further acquire the pathological diagnosis of the suspicious lesions. For the patients with lateral neck lymph node metastasis, computed tomography of the thyroid was performed and the scanning range was from the mastoid of the temporal bone to the innominate artery. Laryngoscopy was used to evaluate the function of the vocal cord. In addition, blood tests, including tests for thyroid and parathyroid hormones, calcitonin and serum calcium levels, were also performed. The serological detection of thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab) and thyroid-stimulating hormone (TSH) were conducted uing a full-automatic chemiluminescence analyzer.

Thyroid surgery

A total thyroidectomy was conducted according to the guidelines of the American Thyroid Association (11). For patients with PTC, an ipsilateral central neck dissection (CND) is routinely performed in Sir Run Run Shaw Hospital. Once the isthmuses located in the lesion or malignant nodules were found in both lobes, a bilateral CND was conducted. If the patients with PTC had clinical evident nodal disease or FNA of a lateral node was indicated to be malignant, a modified lateral neck dissection (levels II–IV) was chosen. All operations included were performed as conventional open surgery by the surgeons of the same medical group.

Tumor grade

Tumor grade was in accordance with the 7th American Joint Committee on Cancer Tumor-Node-Metastasis (AJCC TNM) stage (12). For T stage of PTC, maximum diameter of a primary PTC and depth of tumor invasion (intraglandular or extraglandular, such as extrathyroidal fat, adjacent strap muscle, tracheal, esophageal or carotid wall) are used to divided PTC into 5 stages (T1a, T1b, T2, T3 and T4). With regard to N stage, there are 3 stages: N0 is without nodal metastasis; N1a refers to CLNM; and N1b indicates PTC metastasis to the regional node(s). The definition of multifocality or bilaterality was the presence of more than one tumor foci within a PTC or PTC in both thyroid lobes, respectively. There was no distant metastasis in any of the patients.

Clinicopathological factors

According to the histopathological results, thyroid parenchyma was divided into two types through diffuse infiltration of lymphocytes and inflammatory cells in the thyroid gland, and included LT and no LT. LT was further classified as HT and non-Hashimoto's type LT (NHLT). HT has a progressive loss of thyroid follicular cells and the presence of germinal centers associated with fibrosis.

Statistical analysis

All data, including tumor characteristics and clinicopathological features, were collated in Microsoft Excel 2021 (Microsoft Corporation). In accordance with thyroid parenchyma in tumor characteristics, different analyses were conducted to compare the clinicopathological features between two groups (PTC without LT and PTC with LT), and among three groups (PTC without LT, PTC with HT, and PTC with NHLT). When comparing two groups, the unpaired Student's t-test, χ2 test, Fisher's exact test and Wilcoxon's rank sum test were used. One-way ANOVA was performed for three groups when data met the requirements of homogeneity of variance and Kruskal-Wallis test was performed when the requirements were not met. Univariate and multivariate logistic regression analyses were performed to identity candidate risk factors. An independent samples t-test was used for TG-Ab, TPO-Ab and TSH in the comparison between PTC with HT and PTC with NHLT. SPSS 18.0 (IBM Inc.) was used to conduct data analyses. P<0.05 was considered to indicate a statistically significant difference.

Results

Comparisons of the clinicopathological features

The age of the 458 patients ranged from 13 to 78 years, with a mean age of 43.9±11.2 years. With regard to the sex preponderance of all the patients, there were more women than men [77.5% (355/458) vs. 22.5% (103/458); Table I]. Overall, two different surgical operations were conducted: i) Total thyroidectomy (including isthmectomy and pyramidal lobectomy) with ipsilateral CND; and ii) total thyroidectomy with bilateral CND. The number of coexistent LT cases among the 458 patients with PTC was 133 (29.0%), of which 35 patients (7.6%) were classified as HT and 98 (21.4%) were classified as NHLT (Table II).

Table I.

Clinicopathological features of patients with PTC with LT (n=133) and without LT (n=325).

Table I.

Clinicopathological features of patients with PTC with LT (n=133) and without LT (n=325).

ParametersPTC without LTPTC with LTP-value
Sex, n (%) <0.001
  Female228 (70.2)127 (95.5)
  Male97 (29.8)6 (4.5)
Age, yearsa44.32±11.3442.62±10.880.291
Maximum diameter, cma10.27±6.319.52±6.450.086
Focality, n (%) 0.029
  Unifocal161 (49.5)51 (38.3)
  Multifocal164 (50.5)82 (61.7)
Multifocal, n (%) 0.267
  Ipsilateral49 (15.1)19 (14.3)
  Bilateral115 (35.4)63 (47.4)
Extrathyroidal extension and/or capsular invasion, n (%) 0.004
  No196 (60.3)99 (74.4)
  Yes129 (39.7)34 (25.6)
CLNM and LLNM, n (%) 0.436
  No141 (43.4)63 (47.4)
  Yes184 (56.6)70 (52.6)
CLNM, n (%) 0.329
  No145 (44.6)66 (49.6)
  Yes180 (55.4)67 (50.4)
CLNM numbera2.07±2.841.68±2.650.157
Dissected CLN numbera11.71±5.6416.83±6.96<0.001
CLNM ratioa17.37±21.7510.71±16.270.014

a Values are presented as the mean ± standard deviation. PTC, papillary thyroid carcinoma; CLN, central lymph node; CLNM, CLN metastasis; LT, lymphocytic thyroiditis; LLNM, lateral lymph node metastasis; CLNM ratio, central metastatic lymph node number/central dissected lymph node number.

Table II.

Clinicopathological features of PTC with HT (n=35) or NHLT (n=98), and without LT (n=325).

Table II.

Clinicopathological features of PTC with HT (n=35) or NHLT (n=98), and without LT (n=325).

ParametersPTC without LTPTC with HTPTC with NHLTP-value
Sex, n (%) <0.001
  Female228 (70.2)33 (94.3)94 (95.9)
  Male97 (29.8)2 (5.7)4 (4.1)
Age, yearsa44.32±11.3442.66±11.5642.60±10.690.321
Maximum diameter, cma10.27±6.318.63±4.589.83±7.000.078
Focality, n (%) 0.090
  Unifocal161 (49.5)14 (40.0)37 (37.8)
  Multifocal164 (50.5)21 (60.0)61 (62.2)
Multifocal, n (%) 0.145
  Ipsilateral49 (15.1)2 (5.7)17 (17.3)
  Bilateral115 (35.4)19 (54.3)44 (44.9)
Extrathyroidal extension and/or capsular invasion, n (%) 0.004
  No196 (60.3)30 (85.7)69 (70.4)
  Yes129 (39.7)5 (14.3)29 (29.6)
CLNM and LLNM, n (%) 0.630
  No141 (43.4)18 (51.4)45 (45.9)
  Yes184 (56.6)17 (48.6)53 (54.1)
CLNM, n (%) 0.504
  No145 (44.6)19 (54.3)47 (48.0)
  Yes180 (55.4)16 (45.7)51 (52.0)
CLNM numbera2.07±2.841.29±1.901.83±2.870.132
Dissected CLN numbera11.71±5.6417.97±8.6016.42±6.27<0.001
CLNM ratioa17.37±21.7510.24±18.3010.88±15.580.009

a Values are presented as the mean ± standard deviation. PTC, papillary thyroid carcinoma; LT, lymphocytic thyroiditis; HT, Hashimoto's thyroiditis; NHLT, non-Hashimoto's type LT; CLN, central lymph node; CLNM, CLN metastasis; LLNM, lateral lymph node metastasis; CLNM ratio, central metastatic lymph node number/central dissected lymph node number.

LT and PTC

At the beginning, all 458 patients with PTC were divided into two groups, PTC without LT and PTC with LT. Based on this grouping method, statistical analyses were conducted using the unpaired Student's t-test, the χ2 test, Fisher's exact test and Wilcoxon's rank sum test. Compared to PTC without LT, the predominance of PTC with LT was higher in women (P<0.001; Table I). The prevalence of extrathyroidal extension and/or capsular invasion was significantly higher in patients without LT (P=0.004; Table I). A larger dissected CLN number was evident in the PTC with LT group (P<0.001; Table I), while the CLN metastasis ratio (metastatic CLN number/dissected CLN number) in PTC with LT was significantly lower than that in PTC without LT (P=0.014; Table I). Compared to patients with PTC without LT, patients with PTC and LT had the tendency to present with multifocality (61.7 vs. 50.5%, P=0.029; Table I) and bigger metastatic lymph nodes (0.66 vs. 0.46 cm; P<0.001; Table III), and LT was associated with multifocality [odds ratio (OR), 1.578; 95% confidence interval (CI), 1.046-2.382; P=0.030; Table IV). However, there was no significant difference in the prevalence of age, maximum diameter and the location of multifocality (ipsilateral or bilateral) between the two groups (P=0.291, P=0.086 and P=0.267 respectively). Meanwhile, the CLNM alone and the CLNM number also exhibited no significant differences between the two groups (P=0.329 and P=0.157, respectively; Table I). With regard to pathological tumor (pT) staging, the group with coexisting LT exhibited a higher incidence of pT1a stage disease (57.9 vs. 38.8%; P<0.001) and a lower incidence of pT1b (15.0 vs. 18.7%; P<0.001), pT2 (1.5 vs. 3.7%; P<0.001), pT3 (19.6 vs. 28.9%; P<0.001) and pT4 (6.0 vs. 9.9%; P<0.001) stage disease (Table V). There was no difference in the distribution of pathological nodal staging and AJCC staging.

Table III.

Clinicopathological features of metastatic lymph nodes in patients with PTC with (n=58) and without (n=158) LT.

Table III.

Clinicopathological features of metastatic lymph nodes in patients with PTC with (n=58) and without (n=158) LT.

ParametersPTC without LTPTC with LTP-value
Size of metastatic lymph nodes, cma0.460.66<0.001
Extranodal extension, n (%) 0.189
  Yes32 (20.3)8 (13.8)
  No126 (79.7)50 (86.2)

a Values are presented as the mean. PTC, papillary thyroid carcinoma; LT, lymphocytic thyroiditis.

Table IV.

Multivariate logistic regression analysis for multifocality papillary thyroid carcinoma.

Table IV.

Multivariate logistic regression analysis for multifocality papillary thyroid carcinoma.

VariablesOR95% CIP-value
Sex (male)0.8460.545-1.3130.456
Age (<45 years)1.1900.822-1.7230.357
LT (present)1.5781.046-2.3820.030

[i] LT, lymphocytic thyroiditis; OR, odds ratio; CI, confidence interval.

Table V.

T and N stage in the comparison between patients with PTC with (n=133) and without (n=325) LT.

Table V.

T and N stage in the comparison between patients with PTC with (n=133) and without (n=325) LT.

ParametersPTC without LTPTC with LTP-value
T stage, n (%)
  T1a126 (38.8)77 (57.9)<0.001
  T1b61 (18.8)20 (15.0)<0.001
  T212 (3.7)2 (1.5)<0.001
  T394 (28.9)26 (19.6)<0.001
  T432 (9.8)8 (6.0)<0.001
N stage, n (%) 0.721
  N0142 (43.7)63 (47.4)
  N1a144 (44.3)51 (38.3)
  N1b39 (12.0)19 (14.3)
AJCC stage, n (%) 0.454
  I221 (68.0)96 (72.2)
  II4 (1.2)0 (0.0)
  III79 (24.3)28 (21.1)
  IV21 (6.5)9 (6.7)

[i] PTC, papillary thyroid carcinoma; LT, lymphocytic thyroiditis; T, tumor; N, nodal; AJCC, American Joint Committee on Cancer.

HT and PTC

To determine the characteristics of HT, the 458 patients with PTC were further classified into three groups: PTC without LT, PTC with HT and PTC with NHLT. Comparisons between groups were performed using one-way ANOVA or Kruskal-Wallis tests. As shown in Table II, significant differences among the three groups with regard to sex (P<0.001), extrathyroidal extension and/or capsular invasion (P=0.004), dissected CLN number (P<0.001) and CLNM ratio (P=0.009) were observed. Although the patients with PTC and coexisting LT were divided into those with HT and NHLT, there was no significant difference between patients with no LT and those with coexistent LT with respect to age, maximum diameter, bilaterality (Table II), N stage and AJCC stage (Table VI), as well as those with extranodal extension (Table VII). Additionally, the TG-Ab and TPO-Ab values in patients with PTC and HT were significantly increased compared with those in patients with PTC and NHLT (P<0.011 and P<0.002, respectively). The TSH level of patients with PTC and HT tended to be lower, but this difference was not statistically significant (P=0.727) (Table SI).

Table VI.

T and N stage of PTC in patients with HT (n=35) or NHLT (n=98) and without LT (n=325).

Table VI.

T and N stage of PTC in patients with HT (n=35) or NHLT (n=98) and without LT (n=325).

ParametersPTC without LTPTC with HTPTC with NHLTP-value
T stage, n (%) 0.001
  T1a126 (38.8)23 (65.7)54 (55.1)
  T1b61 (18.7)7 (20.0)13 (13.3)
  T212 (3.7)0 (0.0)2 (2.0)
  T394 (28.9)5 (14.3)21 (21.4)
  T432 (9.8)0 (0.0)8 (8.2)
N stage, n (%) 0.667
  N0142 (43.7)17 (48.6)46 (46.9)
  N1a144 (44.3)15 (42.9)36 (36.8)
  N1b39 (12.0)3 (8.6)16 (16.3)
AJCC stage, n (%) 0.539
  I221 (68.0)23 (65.7)73 (74.5)
  II4 (1.2)0 (0.0)0 (0.0)
  III79 (24.3)11 (31.4)17 (17.3)
  IV21 (6.5)1 (2.9)8 (8.2)

[i] PTC, papillary thyroid carcinoma; LT, lymphocytic thyroiditis; HT, Hashimoto's thyroiditis; NHLT, non-Hashimoto's type LT.

Table VII.

Clinicopathological features of metastatic lymph nodes in patients with HT (n=14) or NHLT (n=44) and without LT (n=158).

Table VII.

Clinicopathological features of metastatic lymph nodes in patients with HT (n=14) or NHLT (n=44) and without LT (n=158).

ParametersPTC without LTPTC with HTPTC with NHLTP-value
Size of metastatic lymph nodes, cma0.460.710.65<0.001
Extranodal extension, n (%) 0.169
  Yes32 (20.3)2 (14.3)6 (13.6)
  No126 (79.7)12 (85.7)38 (86.4)

a Values are presented as the mean. PTC, papillary thyroid carcinoma; LT, lymphocytic thyroiditis; HT, Hashimoto's thyroiditis; NHLT, non-Hashimoto's type LT.

Risk factors for lymph node metastases in PTC

The five factors (sex, age, tumor size, LT presence and multifocality) were included to perform a multivariate logistic regression analysis. The male sex (OR, 2.000; 95% CI, 1.216-3.288; P=0.006), an age of <45 years (OR, 0.592; 95% CI, 0.398-0.879; P=0.009) and a tumor diameter >1 cm (OR, 3.913; 95% CI, 2.431-5.734; P<0.001) were significantly associated with CLNM in patients with PTC (Table VIII).

Table VIII.

Multivariate logistic regression analysis for central lymph node metastasis.

Table VIII.

Multivariate logistic regression analysis for central lymph node metastasis.

VariablesOR95% CIP-value
Sex (male)2.0001.216-3.2880.006
Age (<45 years)0.5920.398-0.8790.009
Tumor diameter (>1 cm)3.9132.431-5.734<0.001
Multifocality (present)0.2940.567-1.1870.294
LT (present)0.8510.568-1.2770.436

[i] LT, lymphocytic thyroiditis; OR, odds ratio; CI, confidence interval.

Discussion

LT is widely acknowledged as an autoimmune thyroid disease that contains a common form of chronic lymphocytic thyroiditis, also known as HT, which was first described by Hakaru Hashimoto in 1912 (13). HT exhibits an association with thyroid dysfunction and the development of thyroid nodules. Currently, PTC is the most common type of thyroid carcinoma, with an incidence rate that has risen markedly in recent years (14). However, the overall cancer-related 10-year survival rate for PTC after surgery and radioactive iodide treatment has reached nearly 90% (15).

Since Dailey et al (1) first found the association between HT and thyroid carcinoma in 1955, debate has risen about the association between PTC and HT. A study by de Alcântara-Jones et al (16) declared that there was no association between HT and PTC, which was similar to the finding in the study by Anil et al (17). Although rarely seen in daily clinical activities, the coexistence of HT in patients with thyroid carcinoma has increased gradually, with a prevalence varying from 9 to 58%, and the mean age of patients being affected ranging from 39.5 to 69.0 years (2), depending on different regions and ethnicities. Di Pasquale et al (18) showed that out of 33 patients with HT who underwent long-term follow-up, there were 33 cases with coexisting thyroid carcinoma, including 30 PTCs. Similar results were reported in the study by Intidhar et al (19), where PTC in patients with HT accounted for 14% of cases, and the meta-analysis further identified that the rate of HT coexisting with PTC was higher than coexistence with benign thyroid disease or other thyroid cancer types (2). The present study found that the prevalence of LT in patients with PTC was 29.0%, while the prevalence of HT was 7.6%. The finding suggested that HT might contribute to be a risk factor for PTC (2), as also indicated in a hypothesis that HT refers to a chronic inflammatory disorder and long persistent inflammatory stimulation to generate a higher serum TSH level, which contributes to the development of PTC (3,20).

To date, the association between coexisting HT with PTC and clinical prognosis remains controversial. A number of studies have suggested that patients with PTC coexisting with HT could exhibit a better prognosis than those with PTC without HT. In a meta-analysis, Lee et al (2) considered that PTCs with coexistent HT had a tight association with a number of factors, such as the female sex, multifocality and high recurrence-free survival rates, which was confirmed in a study by Huang et al (21), which suggested that HT coexisting with PTC is associated with a favorable prognosis. Moreover, previous studies indicated that lymphocytic infiltration led to a low frequency of recurrence and an improvement in disease-free survival rate (22,23). However, the higher rate of multifocality (24) in LT-associated PTC cases raises the opposite view due to its tendency to result in a poor prognosis. It was previously reported by Del Rio et al (25) that HT had no effect on the aggressiveness of PTC. With regard to the present study, PTC concomitant with LT was associated with the female sex, a low capsular invasion rate and a low CLNM ratio, but larger metastatic lymph nodes and a higher rate of multifocality. The reasons for these differences could partly be explained by variations in the study design, or the variability of patients with PTC coexisting with LT and different multifocal forms of PTC.

Despite the fact that few published studies have demonstrated the associations between metastatic lymph node size in patients with PTC with or without LT, the present study found that LT in patients with PTC was associated with larger metastatic lymph nodes, contrary to the low CLNM ratio. Metastatic lymph nodes often enlarge due to an immune reaction to various stimuli in thyroid carcinoma and lymphocytic thyroiditis. Sugitani et al (26) and Randolph et al (27) identified that larger lymph nodes (>3 cm in diameter) have a higher risk of recurrence. However, a challenging study also indicated that small lymph nodes are at risk of harboring aggressive disease biology (28). It still remains unknown as to whether large metastatic lymph nodes can have adverse histological features.

The specific mechanism between HT in PTC and the host immune reaction remains unclear (21). It was reported that the balance between pro-inflammatory and anti-inflammatory factors, including IL-4 and IL-6, in PTC with HT is disrupted, which has a tendency to exacerbate the autoimmune response (29). However, the main molecular findings involved in this autoimmune response are the mutation of the BRAF oncogene, the rearrangement of RET/PTC and the expression of p63. Previous studies revealed a high prevalence of the BRAFV600E mutation in PTC lymph node metastasis, although the association between the two remains unknown (30). Furthermore, studies by Wirtschafter et al (31) and Arif et al (32) identified expression of the RET/PTC fusion gene rearrangements in patients with HT. Similarly, Bozec et al (33) indicated that HT might play an important role in the MAPK signaling pathway for PTC. Moreover, p63 expression documented by Unger et al (34) seemed to be commonly expressed in PTC and in HT, which was further confirmed by Burstein et al (35).

Some of the cases of PTC present with tumor multifocality, with a prevalence that varies from 18 to 87% (36,37). Most cases of MPTC consist of a major lesion accompanied by some nodules, while others are of diffuse microcarcinomas. It was previously reported that MPTC could be more commonly observed in PTC coexistent with LT than solitary PTC (38). The present study documented a significantly higher occurrence of multifocal tumors among patients with concomitant LT, and LT was significantly associated with multifocality (OR, 1.578; 95% CI, 1.046-2.382; P=0.030), which was a similar result to that found by Asanuma et al (39). By contrast, some studies indicated a higher rate of HT in patients with MPTC (40). However, the association between coexisting HT with PTC or MPTC remains controversial. Jeong et al (5) found that the coexistence of LT in patients with PTC did not affect multifocality. A study suggested that HT might contribute to the development of MPTC through the change in the environment of the gland due to the inflammation (8). Tumor-associated LT is frequently observed in the tumor microenvironment of PTC. In HT, infiltration of lymphocytes results in destruction of the thyroid tissue and consequent hypothyroidism, while in PTC with LT, there is not usually an association with the development of concurrent hypothyroidism (41). In the present study, LT was defined as a diffuse infiltration of lymphocytes and inflammatory cells in the thyroid parenchyma, and HT was a progressive loss of thyroid follicular cells and the presence of germinal centers associated with fibrosis. These definitions suggest that the thyroid follicular cells in PTC with HT have progressive and caused further injury. Additionally, it was found that multifocality were more frequently observed in patients with PTC and LT than in those with PTC without LT. Therefore, it is important for doctors to pay more attention to observe the tumor multifocality in PTC coexisting with LT in the process of the operative examination, and a more aggressive surgery and postoperative monitoring are necessary.

The present study plainly indicated that multifocality was not a significant risk factor of CLNM. Multifocality was previously reported as a factor for aggressive disease in PTC (42), while other studies showed a significant difference between unifocality and multifocality in patients with PTC (43). However, Sherman et al (44) believed that the multifocality of PTC was associated with unfavorable outcomes. In the retrospective study by Kuo et al (45), multifocal PTC had a higher rate of lymph node metastases, and easily presented with soft-tissue invasion and distant metastases compared with unifocal PTC. This was confirmed in the study by Kim et al (46), which found that multifocal PTC was associated with cervical lymph node metastasis, extrathyroidal extension and advanced TNM stage. Furthermore, Qu et al (47) and Hay et al (48) revealed that multifocal tumors were more prone to relapse compared with unifocal tumors. Most recently, Al Afif et al (49) demonstrated that the number of tumor foci for PTC was positively associated with the metastasis rate when the number was >2 foci. In conclusion, tumor foci could be used as a risk factor for a poorer prognosis. Therefore, it is necessary for the surgeon to conduct more detailed imaging tests and an FNA biopsy to confirm the multifocality of a lesion, and to pay more attention to tumor multifocality during the therapy of PTC with coexistent LT.

The present study had several limitations. First, the study was retrospective study and from a single center, whereas a multicenter prospective study would be more convincing. Second, further experimental studies should be performed to evaluate the mechanism of the molecular biology. Third, the prognoses of patients with PTC were not documented in the study, and more information might indicate the effect of HT. Finally, the study found that LT was associated with a reduced risk of CLNM; nevertheless, the influence of larger metastatic lymph nodes and a tendency for multifocality remain unknown.

In conclusion, the present study provided an analysis of the association between LT and PTC. The findings demonstrated that PTC concomitant with LT was associated with the female sex, a lower capsular invasion rate, a lower CLNM ratio, larger metastatic lymph nodes and a tendency for multifocality, thus indicating the complexity of the effect of LT on PTC prognosis.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

This study was supported by the Project from the Health Commission of Zhejiang Province (grant no. 2020KY588).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

LX and KW designed the study. KW, LS and JW collected the data and performed the analysis. All authors contributed to the manuscript and approved the submitted version. LX and KW confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Sir Run Run Shaw Hospital, Medical School of Zhejiang University (Hangzhou, China; approval no. 20200716-019). Written informed consent was obtained from all patients before the study.

Patient consent for publication

Written informed consent was obtained from all patients before the study.

Competing interests

Not applicable.

References

1 

Dailey ME, Lindsay S and Skahen R: Relation of thyroid neoplasms to Hashimoto disease of the thyroid gland. AMA Arch Surg. 70:291–297. 1955. View Article : Google Scholar : PubMed/NCBI

2 

Lee JH, Kim Y, Choi JW and Kim YS: The association between papillary thyroid carcinoma and histologically proven Hashimoto's thyroiditis: A meta-analysis. Eur J Endocrinol. 168:343–349. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Zhang L, Li H, Ji QH, Zhu YX, Wang ZY, Wang Y, Huang CP, Shen Q, Li DS and Wu Y: The clinical features of papillary thyroid cancer in Hashimoto's thyroiditis patients from an area with a high prevalence of Hashimoto's disease. BMC Cancer. 12:6102012. View Article : Google Scholar : PubMed/NCBI

4 

Zhang Y, Dai J, Wu T, Yang N and Yin Z: The study of the coexistence of Hashimoto's thyroiditis with papillary thyroid carcinoma. J Cancer Res Clin Oncol. 140:1021–1026. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Jeong JS, Kim HK, Lee CR, Park S, Park JH, Kang SW, Jeong JJ, Nam KH, Chung WY and Park CS: Coexistence of chronic lymphocytic thyroiditis with papillary thyroid carcinoma: Clinical manifestation and prognostic outcome. J Korean Med Sci. 27:883–889. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Jara SM, Carson KA, Pai SI, Agrawal N, Richmon JD, Prescott JD, Dackiw A, Zeiger MA, Bishop JA and Tufano RP: The relationship between chronic lymphocytic thyroiditis and central neck lymph node metastasis in North American patients with papillary thyroid carcinoma. Surgery. 154:1272–1282. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Park JY, Kim DW, Park HK, Ha TK, Jung SJ, Kim DH and Bae SK: Comparison of T stage, N stage, multifocality, and bilaterality in papillary thyroid carcinoma patients according to the presence of coexisting lymphocytic thyroiditis. Endocr Res. 40:151–155. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Muzza M, Degl'Innocenti D, Colombo C, Perrino M, Ravasi E, Rossi S, Cirello V, Beck-Peccoz P, Borrello MG and Fugazzola L: The tight relationship between papillary thyroid cancer, autoimmunity and inflammation: clinical and molecular studies. Clin Endocrinol (Oxf). 72:702–708. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Guo K and Wang Z: Risk factors influencing the recurrence of papillary thyroid carcinoma: A systematic review and meta-analysis. Int J Clin Exp Pathol. 7:5393–5403. 2014.PubMed/NCBI

10 

Zhu J, Wang X, Zhang X, Li P and Hou H: Clinicopathological features of recurrent papillary thyroid cancer. Diagn Pathol. 10:962015. View Article : Google Scholar : PubMed/NCBI

11 

Wang J, Gao L, Song C and Xie L: Incidence of metastases from 524 patients with papillary thyroid carcinoma in cervical lymph nodes posterior to the sternoclavicular joint (level VIa): Relevance for endoscopic thyroidectomy. Surgery. 159:1557–1564. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Edge SB and Compton CC: The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Takami HE, Miyabe R and Kameyama K: Hashimoto's thyroiditis. World J Surg. 32:688–692. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Peng C, Yi D, Zhou Y, Yao J, Chen B, Yang C and Xu D: Differential diagnosis of non-diffuse primary thyroid lymphoma and papillary thyroid carcinoma by ultrasound combined with computed tomography. BMC Cancer. 22:9382022. View Article : Google Scholar : PubMed/NCBI

15 

Ito Y, Kudo T, Kihara M, Takamura Y, Kobayashi K, Miya A and Miyauchi A: Improvement of lymph node recurrence rate, but not distant recurrence and carcinoma death rates, in patients with papillary thyroid carcinoma after disease-free survival for 5 years. Endocr J. 59:895–901. 2012. View Article : Google Scholar : PubMed/NCBI

16 

de Alcântara-Jones DM, de Alcântara-Nunes TF, Rocha Bde O, de Oliveira RD, Santana AC, de Alcântara FT, de Faria TM, da Silva IC and Araújo LM: Is there any association between Hashimoto's thyroiditis and thyroid cancer? A retrospective data analysis. Radiol Bras. 48:148–153. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Anil C, Goksel S and Gursoy A: Hashimoto's thyroiditis is not associated with increased risk of thyroid cancer in patients with thyroid nodules: A single-center prospective study. Thyroid. 20:601–606. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Di Pasquale M, Rothstein JL and Palazzo JP: Pathologic features of Hashimoto's-associated papillary thyroid carcinomas. Hum Pathol. 32:24–30. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Intidhar Labidi S, Chaabouni AM, Kraiem T, Attia N, Gritli S, El May A and Ben Slimane F: Thyroid carcinoma and Hashimoto thyroiditis. Ann Otolaryngol Chir Cervicofac. 123:175–178. 2006.(In French). View Article : Google Scholar : PubMed/NCBI

20 

Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC and Franklyn JA: Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab. 91:4295–4301. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Huang BY, Hseuh C, Chao TC, Lin KJ and Lin JD: Well-differentiated thyroid carcinoma with concomitant Hashimoto's thyroiditis present with less aggressive clinical stage and low recurrence. Endocr Pathol. 22:144–149. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Gupta S, Patel A, Folstad A, Fenton C, Dinauer CA, Tuttle RM, Conran R and Francis GL: Infiltration of differentiated thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival for children and young adults. J Clin Endocrinol Metab. 86:1346–1354. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Matsubayashi S, Kawai K, Matsumoto Y, Mukuta T, Morita T, Hirai K, Matsuzuka F, Kakudoh K, Kuma K and Tamai H: The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland. J Clin Endocrinol Metab. 80:3421–3424. 1995. View Article : Google Scholar : PubMed/NCBI

24 

American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, . Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, et al: Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 19:1167–1214. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Del Rio P, Cataldo S, Sommaruga L, Concione L, Arcuri MF and Sianesi M: The association between papillary carcinoma and chronic lymphocytic thyroiditis: Does it modify the prognosis of cancer? Minerva Endocrinol. 33:1–5. 2008.PubMed/NCBI

26 

Sugitani I, Kasai N, Fujimoto Y and Yanagisawa A: A novel classification system for patients with PTC: Addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery. 135:139–148. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, Tufano RP and Tuttle RM; American Thyroid Association Surgical Affairs Committee's Taskforce on Thyroid Cancer Nodal Surgery, : The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 22:1144–1152. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Alpert EH, Wenig BM, Dewey EH, Su HK, Dos Reis L and Urken ML: Size distribution of metastatic lymph nodes with extranodal extension in patients with papillary thyroid cancer: A pilot study. Thyroid. 25:238–241. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Stassi G, Todaro M, Zerilli M, Ricci-Vitiani L, Di Liberto D, Patti M, Florena A, Di Gaudio F, Di Gesù G and De Maria R: Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res. 63:6784–6790. 2003.PubMed/NCBI

30 

Oler G, Camacho CP, Hojaij FC, Michaluart P Jr, Riggins GJ and Cerutti JM: Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with BRAF mutational status and lymph node metastasis. Clin Cancer Res. 14:4735–4742. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Wirtschafter A, Schmidt R, Rosen D, Kundu N, Santoro M, Fusco A, Multhaupt H, Atkins JP, Rosen MR, Keane WM and Rothstein JL: Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto's thyroiditis. Laryngoscope. 107:95–100. 1997. View Article : Google Scholar : PubMed/NCBI

32 

Arif S, Blanes A and Diaz-Cano SJ: Hashimoto's thyroiditis shares features with early papillary thyroid carcinoma. Histopathology. 41:357–362. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Bozec A, Lassalle S, Hofman V, Ilie M, Santini J and Hofman P: The thyroid gland: A crossroad in inflammation-induced carcinoma? An ongoing debate with new therapeutic potential. Curr Med Chem. 17:3449–3461. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Unger P, Ewart M, Wang BY, Gan L, Kohtz DS and Burstein DE: Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: A pathobiologic link? Hum Pathol. 34:764–769. 2003. View Article : Google Scholar : PubMed/NCBI

35 

Burstein DE, Nagi C, Wang BY and Unger P: Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis. Hum Pathol. 35:465–473. 2004. View Article : Google Scholar : PubMed/NCBI

36 

McCarthy RP, Wang M, Jones TD, Strate RW and Cheng L: Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas. Clin Cancer Res. 12:2414–2418. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Mazeh H, Samet Y, Hochstein D, Mizrahi I, Ariel I, Eid A and Freund HR: Multifocality in well-differentiated thyroid carcinomas calls for total thyroidectomy. Am J Surg. 201:770–775. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Kim KW, Park YJ, Kim EH, Park SY, Park DJ, Ahn SH, Park DJ, Jang HC and Cho BY: Elevated risk of papillary thyroid cancer in Korean patients with Hashimoto's thyroiditis. Head Neck. 33:691–695. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Asanuma K, Sugenoya A, Kasuga Y, Itoh N, Kobayashi S and Amano J: The relationship between multiple intrathyroidal involvement in papillary thyroid carcinoma and chronic non-specific thyroiditis. Cancer Lett. 122:177–180. 1998. View Article : Google Scholar : PubMed/NCBI

40 

Zhu F, Shen YB, Li FQ, Fang Y, Hu L and Wu YJ: The effects of hashimoto thyroiditis on lymph node metastases in unifocal and multifocal papillary thyroid carcinoma: A retrospective Chinese cohort study. Medicine (Baltimore). 95:e26742016. View Article : Google Scholar : PubMed/NCBI

41 

Banerjee S, Nahar U, Dahiya D, Mukherjee S, Dey P, Gupta R, Radotra B, Sachdeva N, Sood A, Bhadada SK and Bhansali A: Role of cytotoxic T cells and PD-1 immune checkpoint pathway in papillary thyroid carcinoma. Front Endocrinol (Lausanne). 13:9316472022. View Article : Google Scholar : PubMed/NCBI

42 

Liu Z, Wang L, Yi P, Wang CY and Huang T: Risk factors for central lymph node metastasis of patients with papillary thyroid microcarcinoma: A meta-analysis. Int J Clin Exp Pathol. 7:932–937. 2014.PubMed/NCBI

43 

Schindler AM, van Melle G, Evequoz B and Scazziga B: Prognostic factors in papillary carcinoma of the thyroid. Cancer. 68:324–330. 1991. View Article : Google Scholar : PubMed/NCBI

44 

Sherman SI, Brierley JD, Sperling M, Ain KB, Bigos ST, Cooper DS, Haugen BR, Ho M, Klein I, Ladenson PW, et al: Prospective multicenter study of thyroiscarcinoma treatment: Initial analysis of staging and outcome. National thyroid cancer treatment cooperative study registry group. Cancer. 83:1012–1021. 1998. View Article : Google Scholar : PubMed/NCBI

45 

Kuo SF, Lin SF, Chao TC, Hsueh C, Lin KJ and Lin JD: Prognosis of multifocal papillary thyroid carcinoma. Int J Endocrinol. 2013:8093822013. View Article : Google Scholar : PubMed/NCBI

46 

Kim HJ, Sohn SY, Jang HW, Kim SW and Chung JH: Multifocality, but not bilaterality, is a predictor of disease recurrence/persistence of papillary thyroid carcinoma. World J Surg. 37:376–384. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Qu N, Zhang L, Ji QH, Zhu YX, Wang ZY, Shen Q, Wang Y and Li DS: Number of tumor foci predicts prognosis in papillary thyroid cancer. BMC Cancer. 14:9142014. View Article : Google Scholar : PubMed/NCBI

48 

Hay ID: Management of patients with low-risk papillary thyroid carcinoma. Endocr Pract. 13:521–533. 2007. View Article : Google Scholar : PubMed/NCBI

49 

Al Afif A, Williams BA, Rigby MH, Bullock MJ, Taylor SM, Trites J and Hart RD: Multifocal papillary thyroid cancer increases the risk of central lymph node metastasis. Thyroid. 25:1008–1012. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April-2023
Volume 25 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wu K, Shi L, Wang J and Xie L: Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study. Oncol Lett 25: 148, 2023
APA
Wu, K., Shi, L., Wang, J., & Xie, L. (2023). Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study. Oncology Letters, 25, 148. https://doi.org/10.3892/ol.2023.13734
MLA
Wu, K., Shi, L., Wang, J., Xie, L."Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study". Oncology Letters 25.4 (2023): 148.
Chicago
Wu, K., Shi, L., Wang, J., Xie, L."Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study". Oncology Letters 25, no. 4 (2023): 148. https://doi.org/10.3892/ol.2023.13734