Coexistence of papillary thyroid cancer with Hashimoto thyroiditis
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Conflicting data have been reported with regard to Hashimoto thyroiditis (HT) and risk of malignancy. The aim of this study was to evaluate coexistence of papillary thyroid cancer (PTC) with HT.
Patients and methods
This is a retrospective cohort study in which HT was diagnosed in 452 (F/M ratio = 405:47, median age 53.5 ± 12.1 years) of 7,545 patients qualified for thyroidectomy throughout the years 2002 to 2010. Pathological reports were reviewed to identify prevalence of PTC in HT vs. non-HT patients.
PTC was diagnosed in 106 of 452 (23.5 %) HT patients vs. 530 of 7,093 (7.5 %) non-HT patients (p < 0.001). Metastases to level VI lymph nodes were observed in 81 of 106 (76.4 %) patients with PTC in HT vs. 121 of 530 (22.8 %) patients with PTC in non-HT disease (p < 0.001).
HT was associated with a threefold increase of PTC prevalence as compared to other non-HT thyroid diseases, and the spread of PTC to level VI lymph nodes was four times more frequent in HT than in non-HT patients.
KeywordsHashimoto thyroiditis Papillary thyroid carcinoma Benign thyroid disease
Autoimmune thyroid disease known as Hashimoto thyroiditis (HT) is one of special forms of chronic thyroiditis and the most common non-iatrogenic cause of hypothyroidism. The condition is definitely more prevalent in female population (M/F ratio of 1:10, 1:20), is seen in each age group, and may also affect children and adolescents. Its unclear etiopathogenesis strongly indicates an autoimmune background, associated with T-helper lymphocyte (CD4+) activation by class II human leukocyte antigen system cells (MHC class II: HLA-DR3, HLA-DR4, HLA-DR5). On the one hand, the cells recruit cytotoxic lymphocytes (Tc, CD8+), thus facilitating a release of cytokines that damage thyroid follicular cells and, on the other hand, activating B lymphocytes; they facilitate production of specific anti-microsomal, anti-thyroglobulin, or anti-TSH receptor antibodies. Described for the first time in 1912, the disease may have two distinct histological forms: atrophic and nodular. Clinically, in the majority of cases, it is characterized by hypothyroidism, although in a small number of patients, it may be preceded by symptoms of hyperthyroidism. The association between coexistence of Hashimoto thyroiditis and papillary thyroid cancer (PTC) was first described by Dailey et al. in 1955. Since that time, attempts have been made at elucidation of this phenomenon. The objective of the present paper was to demonstrate coexistence of HT with an autoimmune background with highly differentiated thyroid cancer and to attempt to determine assumptions for further therapeutic management and prognosis in patients operated on for Hashimoto thyroiditis and papillary thyroid cancer.
An early detection of lesions, a careful selection of a surgical strategy in a referral center, target-based adjuvant therapy, and treatment monitoring may have a significant impact on improvement of therapeutic outcomes and quality of life in patients with the disease [1, 2].
Materials and methods
Demographic characteristics of 7,545 patients analyzed in this study
HT (n = 452)
Non-HT (n = 7,093)
Gender ratio (M/F)
Average age (years)
53.5 ± 12.1
52.3 ± 15.5
Preoperative thyroid volume in ml (by ultrasound), mean ± SD
22.1 ± 18.2
96.2 ± 40.4
Preoperative diagnosis, n (%)
Benign thyroid disease (BTD)
Positive FNAB for PTC
All the patients qualified for surgical treatment were subjected to thyroid ultrasonography, determinations of free thyroid hormones (fT4, fT3), thyrotropic hormone (TSH), as well as anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies. The inclusion criteria for surgery in the HT group included nodular lesions of the thyroid detected by ultrasound as hypoechoic or hyperechoic nodular pattern at least 5 mm in diameter, identification of a perinodular hypoechogenic or hyperechogenic halo, and the presence of an anechoic lesion with a reinforced posterior wall. A repeated analysis of fine-needle aspiration biopsy (FNAB) results based on the Bethesda 2009 classification showed that in the test results, the predominating lesions were these that today would be classified as groups III and IV of the above classification system. In the non-HT group, surgical treatment was indicated in case of suspicious lesions detected by FNAB (groups III–VI according to Bethesda 2009), symptoms of tracheal and surrounding tissue compression, multinodular toxic goiter, and Graves’ disease. Prior to surgical treatment, all the patients presenting with clinical and biochemical hypothyreosis received levothyroxine substitution. The mean follow-up time in the analyzed group was 4.3 ± 2.1 years. In the first postoperative day, indirect laryngoscopy was performed in all the patients and their calcium levels were determined; hypocalcemia was assumed at total calcium levels below 2.0 mmol/l. Following thyroidectomy and the diagnosis of differentiated thyroid carcinoma, a uniform model of therapeutic management was employed in all the patients; the model consisted of radioiodine adjuvant treatment in case of tumors with a diameter of >10 mm, administration of l-thyroxine (at a dose ensuring the suppression level for TSH range of 0.1–0.3 mU/l), and strict periodic follow-up determination of hormones and anti-TG.
Statistical analysis for normally distributed variables employed the Student’s t test in comparisons, while the remaining variables were analyzed using the χ2 test. When the test assumptions were not fulfilled, comparisons were based on the so-called Fisher’s exact test. The criterion of including a variable into the model was p < 0.05.
In the analyzed group of 452 patients with Hashimoto thyroiditis, 106 (23.5 %) cases of papillary thyroid cancer (HT-PTC) were detected as compared to 530 (7.5 %) cancer patients in the group of 7,093 individuals (non-HT-PTC) without diagnosed autoimmune disease. The values are statistically significant (p < 0.001). Both the analyzed groups showed a similar ratio of males to females (1:9 in HT-PTC group vs. 1:10 in non-HT-PTC group) and a similar mean age of the patients (53.5 ± 12.1 years in HT-PTC group vs. 52.3 ± 15.5 years in non-HT-PTC group). A statistically significant difference was observed in preoperative goiter volume as determined by ultrasonography (22.1 ± 18.2 ml in HT-PTC group vs. 96.2 ± 40.4 ml in non-HT-PTC group, p < 0.001). FNAB was performed in all the patients with nodular lesions above 5 mm in diameter, but in the HT-PTC group, only 31 (29.2 %) of 106 HT-PTC subjects had thyroid tumor diagnosed preoperatively. In the remaining cases, cytological material did not raise any suspicions of neoplastic process. In FNAB smears, oxyphilic cells with lymphocytes and macrophages predominated (Table 1). In eight (12.3 %) patients (pT1a = 65) with a nodule of 8–10 mm in size, FNAB confirmed thyroid microcarcinoma. In one case, in a 4-mm nodule, a focus of papillary thyroid carcinoma was detected preoperatively. The above lesions were seen in females in a lower age range as compared to the entire group (16–46 years).
Final histopathology diagnosis after thyroidectomy in 7,545 patients involved in this study
HT (n = 452)
Non-HT (n = 7,093)
Papillary thyroid cancer, no. (%)
Regional lymph nodes
Diameter of the largest foci in mm (mean ± SD)
7.6 ± 5.8
9.4 ± 6.9
Number of removed lymph nodes within level VI (mean ± SD)
12.7 ± 3.7
6.5 ± 2.4
Number of macrometastatic lymph nodes (mean ± SD)
6.4 ± 2.7
2.1 ± 1.0
Complications after thyroidectomy in 636 patients involved in this study
PTC in HT (n = 106)
PTC in non-HT (n = 530)
Parathyroid found in pathological report, no. (%)
Hypoparathyroidism after operation, no. (%)
Unilateral RLN injury, no. (%)
Coexistence Hashimoto thyroiditis with papillary thyroid cancer
Patient included in the study
HT with PTC, n (%)
Dailey at al. 
278 with PTC
Singh et al. 
388 with PTC
Chesky VE et al. 
432 with HT
Ott et al. 
161 with TC
Eisenberg et al. 
120 with TC
Sclafani et al. 
48 with HT
Schäffler et al. 
153 with TC
Matesa-Anić et al. 
Cipolla et al. 
71 with PTC
Pisanu et al. 
344 with PTC
Kebebew et al. 
136 with PTC
Matsubayashi et al. 
95 with PTC
Yoon et al. 
195 with PTC
Paulson et al. 
139 with PTC
Repplinger et al. 
217 with HT
Another extremely important element that plays a role in clinical assessment of papillary thyroid cancer is the size of the primary focus. Tumors up to 10 mm in diameter are characterized by a favorable prognosis, although they may demonstrate all specific properties of a malignancy, with possible nodal metastasizing, capsular infiltration, or multifocal growth in the thyroid tissue. Bradley et al.  analyzed a group of accidentally detected forms of papillary thyroid cancer (687 patients, 81 IPTC (12 %)) and confirmed this tumor form in as many as 21 (28 %) patients of 74 individuals with Hashimoto thyroiditis. The primary focus size did not exceed 7 mm. (mean 2.8 ± 1.7 mm). In the present analysis, although the mean focus size was larger as compared to the above-mentioned values, it did not exceed 10 mm in diameter, thus providing the basis for microcarcinoma diagnosis. In the analyzed material, microcarcinomas were markedly predominant (65 cases = 61.3 %). Of significance is also a relatively high number (22 = 20.8 %) of patients with multifocal PTC form and with foci with the diameter starting from 2 to 5 mm. Based on the analysis, one may thus surmise that coexistence of an autoimmune disease and papillary thyroid cancer did not limit the number of primary foci and affected their size only [29, 30]. The above data have been quite extensively confirmed in the literature on the subject. Numerous authors are inclined to believe that coexistence of lymphocytic infiltrations, positive history of thyroid autoimmune diseases, or significantly high antibody levels (anti-TPO, anti-TG) prior to surgery had a significant impact on prognosis improvement. Although there have been voiced opinions that such factors did not affect mortality rates, they undoubtedly determined early initiation of targeted therapy .
Tumor grading determined by the degree of capsular infiltration and nodal metastasizing allows for selecting patients with a poor prognosis. As it has been mentioned previously, papillary thyroid cancer is generally characterized by a good prognosis. This is particularly true in patients with highly differentiated pT1a cancers that do not exceed 10 mm in diameter. It should be noted, however, that even these forms show a fairly high ability to metastasize. In their analysis of 203 patients with papillary thyroid microcarcinoma, So et al. found nodal metastases in as many as 24.6 % of subjects, multifocal cancer in 31 %, and capsular infiltrations in 20.7 % of their surgical patients . Similar observations were made by Mercante et al. and Cho et al. [32, 33], who emphasized that the size of the primary focus did not play a role in the presence or absence of nodal metastases or capsular infiltrations. Is there, then, any difference in tumor morphology, ability to metastasize, and prognosis in patients with papillary thyroid cancer and Hashimoto thyroiditis?
In the entire presently analyzed material, the presence of central compartment lymph node metastases was significantly higher in patients with cancer and Hashimoto thyroiditis (PTC-HT = 81 (76.4 %) vs. non-HT-PTC = 121 (22.8 %)). According to numerous reports, metastatic foci in cervical lymph nodes accompany both “clear” cancer forms and tumors presenting with symptoms of chronic lymphocytic thyroiditis. The degree of nodal involvement—differently reported in various publications—ranged from 7 to 49 % [34, 35, 36]. In one of the recent articles, Paulson et al.  suggest that a lower number of nodal metastases to the central compartment are a result of a coexisting autoimmune disease and the protective role it plays in neoplastic spreads beyond the primary focus area.
Based on our observations of both groups of patients, a conclusion has been formulated that concomitant Hashimoto’s thyroiditis and papillary thyroid carcinoma are more common phenomena than previously believed, since they are observed in approximately 20 % of all cases of this cancer type. According to data from the literature on the subject, it is significantly more common among women from younger age groups, is characterized by lesions with a small diameter of the primary focus, and, at times, has a multifocal form, but the prognosis is statistically more favorable as compared to other patient groups [20, 38]. Improved ultrasound techniques, higher availability of examinations, and higher awareness of patients today allow for early institution of appropriate treatment. The above-described observations of the present authors, as well as data from world literature, indicate a need for further immunological and genetic investigations aiming at understanding the nature of a protective role of coexistence of an autoimmune disease and thyroid cancer. It should be remembered, however, that the continuously low number of patients, high costs of genetic probes, and ambiguous diagnostic protocol limit the use of such observations in clinical practice. Hence, in view of the high percentage of PTC in HT and incidence of complications following total thyroidectomies that is comparable to that observed in operations performed in patients with nonneoplastic goiter [39, 40, 41], the optimum strategy of surgical treatment of Hashimoto thyroiditis in such patients should include total thyroidectomy and preventive central compartment lymphadenectomy, which is of importance in assessing tumor stage and determining recommendations for further adjuvant therapy. Total thyroidectomy along with excision of central compartment lymph nodes may result in damaging recurrent laryngeal nerves and accidental excision of inferior parathyroids glands. Nevertheless, the incidence of such complications in referral centers is low.
The literature on the subject increasingly more often presents reports stating that primary total thyroidectomy allows not only for treating the neoplastic disease already diagnosed based on the FNAB result but also contributes to a decrease in reoperation rate due to postoperative diagnosis of thyroid cancer. Analyzing this aspect, we may say that primary total thyroidectomy also limits the number of permanent complications, which in a significant percentage of cases pose a considerable threat in the course of reoperation. In our opinion, the above-described rationale provides a foundation for considering radical surgical treatment in cases of nodular lesions being present in immunologically altered thyroid gland.
Conflicts of interest
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- 3.Chesky VE, Hellwig CA, Welch JW (1961) Cancer of the thyroid associated with Hashimoto’s disease: an analysis of forty eight cases. Am Surg 28:678–85Google Scholar
- 10.Segal K, Ben-Bassat M, Avraham A, Hard-El G, Sidi J (1985) Hashimoto’s thyroiditis and carcinoma of the thyroid gland. Intl Surg 70:205–9Google Scholar
- 15.Cyniak-Magierska A, Wojciechowska-Durczyńska K, Krawczyk-Rusiecka K, Zygmunt A, Lewiński A (2011) Assessment of RET/PTC1 and RET/PTC3 rearrangements in fine-needle aspiration biopsy specimens collected from patients with Hashimoto’s thyroiditis. Thyroid Res 10(1):4–5Google Scholar
- 32.Mercante G, Frasoldati A, Pedroni C, Formisano D, Renna L, Piana S, Gardini G, Valcavi R, Barbieri V (2009) Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid 19(7):707–716PubMedCrossRefGoogle Scholar
- 40.Barczyński M, Konturek A, Hubalewska-Dydejczyk A, Gołkowski F, Cichoń S, Nowak W (2010) Five-year follow-up of a randomized clinical trial of total thyroidectomy versus Dunhill operation versus bilateral subtotal thyroidectomy for multinodular nontoxic goiter. World J Surg 34:1203–1213PubMedCrossRefGoogle Scholar