| Abstract|| |
Introduction: Chronic lymphocytic thyroiditis [Hashimoto thyroiditis (HT)] is a common thyroid lesion diagnosed on fine-needle aspiration cytology (FNAC). Apart from FNAC, various other parameters, such as clinical features, ultrasonographic findings, antithyroid antibody levels, hormone profiles, and radionuclide thyroid scan, are also taken into consideration in making a diagnosis of HT.
Aims: To grade lymphocytic thyroiditis based on the cytomorphology and to correlate the cytological grades with the levels of antithyroid peroxidase antibody (ATPO), antithyroglobulin antibody (ATG), and thyroid stimulating hormone (TSH).
Materials and Methods: During a period of one and half years, 1,667 cases underwent FNAC of thyroid at our tertiary care center. Of these, 128 cases had cytological evidence of lymphocytic thyroiditis. Out of these, in 60 cases the levels of ATPO, ATG, and TSH were known. The cytological grades of lymphocytic thyroiditis in these cases were correlated with these parameters.
Results: Out of the 60 cases, 55 were females. Age ranged from 5 years to 70 years, with majority of patients in third decade. Diffuse enlargement of thyroid was the commonest presentation. However, 14 cases presented with nodular disease. Majority of the patients had grade 1 thyroiditis (27 cases), followed by grade 2 thyroiditis (22 cases). Cytomorphology was diagnostic of thyroiditis in all 60 cases. ATPO was elevated in 57 cases and ATG was elevated in 40 cases. Elevated level of TSH was seen in only 18 cases. In 39 cases, TSH value was normal. There was no correlation between the cytological grades of thyroiditis and the levels of antithyroid antibodies and TSH.
Conclusion: Lymphocytic infiltration of thyroid follicles is pathognomonic of lymphocytic thyroiditis. Positivity for antithyroid antibodies is strongly associated with HT but no correlation was observed between the grades of thyroiditis and the levels of ATPO, ATG, and TSH.
Keywords: Biochemical parameters, cytological grade, lymphocytic thyroiditis
|How to cite this article:|
Anila K R, Nayak N, Jayasree K. Cytomorphologic spectrum of lymphocytic thyroiditis and correlation between cytological grading and biochemical parameters. J Cytol 2016;33:145-9
|How to cite this URL:|
Anila K R, Nayak N, Jayasree K. Cytomorphologic spectrum of lymphocytic thyroiditis and correlation between cytological grading and biochemical parameters. J Cytol [serial online] 2016 [cited 2019 Jul 22];33:145-9. Available from: http://www.jcytol.org/text.asp?2016/33/3/145/188055
| Introduction|| |
Hashimoto thyroiditis (HT), considered a synonym of chronic lymphocytic thyroiditis, was described for the first time by Hakaru Hashimoto in 1912. HT is an organ-specific immunologically mediated inflammatory disease. The initiating event is thought to be due to sensitization of cluster of differentiation 4 (CD4)+ T-helper cells to thyroid antigens. The effector mechanisms for thyrocyte destruction includes CD8+ T-cell mediated cytotoxicity, cytokine mediated cell death, and antibody dependent cell-mediated cytotoxicity caused by binding of antithyroid antibodies, antithyroglobulin, antithyroid peroxidase, and anti-thyroid stimulating hormone (TSH) receptor antibodies to thyrocyte surface.
HT is characteristically seen in cytology smears as the presence of a mixed population of mature and transformed lymphocytes, Hurthle cells, follicular cells with fine chromatin, anisonucleosis, and epithelioid cell collections and giant cells. Presence of all or some of these features along with biochemical, ultrasonographic, and clinical features help in making a diagnosis.
The cytological grading of thyroiditis on smears based on a set of predefined criteria was done for the first time by Bhatia et al., wherein the cytological grades of lymphocytic thyroiditis was correlated with the clinical, biochemical, ultrasonographic, and radionuclide parameters and serum thyroid microsomal antibody values.  Sood and Nigam in their study correlated the cytological grades with TSH and antithyroid peroxidase antibody (ATPO) values.  In the present study, we have correlated the cytological grades of lymphocytic thyroiditis as per the criteria of Bhatia et al. with TSH, ATPO, and antithyroglobulin antibody (ATG) values.
| Materials and Methods|| |
During the period from January 2014 to August 2015 (one and half years) a total of 1,667 patients were referred to the cytopathology division for fine-needle aspiration cytology (FNAC) of thyroid. FNAC of the thyroid is done using 23 G needle. Both aspiration and non-aspiration techniques are used. A maximum of two attempts are made to procure material. The smears are fixed in ethanol and stained with Papanicolaou stain.
During this period, 128 cases showed cytological features of lymphocytic thyroiditis. The criteria used for making a diagnosis of chronic lymphocytic thyroiditis are the presence of increased lymphocytes in the background; lymphocytes/plasma cells infiltrating follicular cells; fine chromatin of follicular cells; and presence of Hurthle cells, anisonucleosis, epithelioid cells, and giant cells. The grading of the thyroiditis was done by the criteria used by Bhatia et al. considering the extent of lymphocytic infiltration ranging from increased lymphocytes in the background to florid lymphocytic infiltration with follicle formation and presence of germinal center fragments. Other features, such as Hurthle cell change and presence of epithelioid cells, are also taken into consideration.
Out of the 128 cases of lymphocytic thyroiditis, only in 60 cases TSH, ATPO, and ATG levels were available for correlation. Hence, in these 60 cases the cytological grades of thyroiditis was correlated with the TSH, ATPO, and ATG levels using Mann-Whitney and chi-square tests, and P value of <0.05 was considered significant.
| Results|| |
Sixty cases of chronic lymphocytic thyroiditis were included in the study. Most of the patients were females [55 cases (92%)]. The most common age group was the third decade of life (31-40 years). Forty-six (77%) patients presented with diffuse enlargement of thyroid, and 14 (23%) cases presented with nodular disease. TSH level was raised in 18 (30%) cases and showed normal values in 39 (65%) cases. ATPO value was raised in 57 (95%) cases and was normal in only 3 (5%) cases. ATG level was raised in 40 (67%) cases and was normal in 20 (33%) cases. Most of the patients had grade 1 thyroiditis [27 cases (45%)], followed by grade 2 thyroiditis [22 cases (36.67%)]. [Table 1] shows the percentage distribution of patients in each of the cytological grades.
Grade 1 thyroiditis was characterized by the presence of increased number of lymphocytes in the background or the presence of lymphoid cells infiltrating follicular cells [Figure 1]a. Smears of patients with grade 2 thyroiditis showed the presence of Hurthle cells, epithelioid cells, giant cells, and anisonucleosis and increased number of lymphocytes [Figure 1]b and c. In our study, we came across only 11 (18.33%) cases of grade 3 thyroiditis that was characterized by the presence of florid lymphocytic infiltration with germinal center formation and the presence of scanty follicular cells [Figure 1]d. [Table 2] shows the comparison between the present study and study by Bhatia et al. The statistical correlation between the grades of thyroiditis and the biochemical parameters was found to be insignificant (P value > 0.1).
|Figure 1: (a) Grade 1 thyroiditis characterized by the presence of increased number of lymphocytes in the background (PAP stain, ×200) (b) Grade 2 thyroiditis showing the presence of Hurthle cells, epithelioid cells, giant cells, and anisonucleosis and increased number of lymphocytes (PAP stain, ×200) (c) Grade 2 thyroiditis showing the presence of Hurthle cells with lymphocytic infiltration (PAP stain, ×400) (d) Grade 3 thyroiditis characterized by the presence of florid lymphocytic infiltration (PAP stain, ×200)|
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|Table 2: Comparison between the present study and the study by Bhatia et al. |
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There was no correlation between the cytological grades of thyroiditis and serum values of ATG, ATPO, and TSH. Irrespective of the cytological grades, maximum number of patients in each of the grades showed a common pattern, increase in ATPO and ATG level with normal TSH value. [Table 3] shows the relation between the cytological grades and the serum ATPO, ATG, and TSH values.
|Table 3: Relation of cytological grading of lymphocytic thyroiditis and values of ATPO, ATG, and TSH |
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Cytomorphological features, such as presence of epithelioid cells, Hurthle cells, and giant cells, were noted in the patients with grade 2 thyroiditis; however, the presence of these features showed no difference in the antibody profile with majority of these cases also showing increased ATPO level with normal TSH values as in grade 1 and grade 3 cases.
| Discussion|| |
HT or chronic lymphocytic thyroiditis is an autoimmune thyroiditis that is clinically characterized by an initial transient phase of hyperthyroidism followed by a chronic phase of hypothyroidism. In the initial phase, there is antibody mediated destruction of thyroid follicles and lymphocytic infiltration. In the chronic phase, there will be only minimal residual and atrophic follicles with fibrosis of the thyroid parenchyma. Depending on the stage of the disease, the patients present with features of hypo- or hyperthyroidism. Clinical presentation, hormonal status, and antithyroid antibody values will vary depending on the stage of the disease.
In this study, we have correlated the cytological grades of thyroiditis as proposed by Bhatia et al. with TSH, ATPO, and ATG values. We have also done a descriptive analysis of the data of the patients included in the study.
Our patients were aged between 5 years and 70 years and were predominantly females. Fifty-five patients were females and only 5 were males. This female predominance was observed in most of the studies in the literature. The most common age group was 31-40 years; this is comparable to the observation made by Bhatia et al. in their study. In a previous study from the United Kingdom, the patients were older women.  According to some authors, this disparity in the age distribution in studies from India and outside is due to iodine deficiency resulting in the onset of thyroiditis at an younger age group in India. , However, we feel that this suggestion needs to be reconsidered since iodine-fortified salt has been introduced in India since many years. Also, there are other views regarding the increase in incidence of HT. This includes excess iodine intake, particularly in coastal areas.  In a study by Li et al., it was noted that subjects who were ATPO and ATG positive at baseline developed thyroid dysfunctions more frequently than seronegative subjects. According to them, high iodine intake was a risk factor for developing hypothyroidism in antibody-positive subjects. A constant exposure to excessive iodine intake in turn increased the incidence of positive ATG.  HT is in fact considered a common cause of hypothyroidism in areas where iodine levels are sufficient. 
Twenty-six percent of the patients presented with nodular disease. This is significantly higher when compared to a study from India by Bhatia et al. where only 2.63% presented with nodular disease. However, there are other studies in the literature wherein 80% of the patients presented with nodular disease.  The authors have opined that nodular disease is usually seen in early stages of HT and that patients coming in later stages of HT, where the clinical and hormonal changes have become established present clinically with diffuse form of HT. We are of the opinion that a significant proportion of our patients may have presented with early stages of the disease, hence there is an increase in the proportion of nodular disease in our study group. This is supported by our observation that in the present study a normal TSH value was observed in 39 cases, while ATPO value was elevated in 95% of cases and nodular disease was observed in 23% of cases. Other authors have also observed that in the early stages of the disease, TSH value may be normal and ATPO antibodies may be positive.  The autoantibodies cause destruction of thyrocytes that in turn lead to abnormalities in the hormonal levels. So in the early stages, the autoantibodies will be elevated with normal hormonal values. Later on, the hormonal abnormalities also set in. This is in agreement with our observation that our series of patients must have presented at an early stage with a significant proportion presenting with nodular disease, normal TSH value, and raised ATPO and ATG antibody values. Fifty-seven patients in this study group had increased ATPO values. This early presentation is understandable since our patients belong to a region of high literacy wherein people seek medical attention for even subtle symptoms. Florid lymphocytic thyroiditis is more common in young patients and present with nodular disease and low or normal antithyroid antibody values.  In classical cases, the patients are middle-aged women with evidence of hypothyroidism, raised antithyroid antibody titers, and elevated TSH values and the cytology shows lymphocytes, plasma cells, Hurthle cell change, and epithelioid histiocytes, etc.
HT can present as solitary nodules. Nodular disease can be mistaken for neoplasm. A combined approach using clinical, radiological, and cytological modalities along with hormonal status and antithyroid antibody values help in making the correct diagnosis. Cytologically, the fine chromatin and anisonucleosis of follicular cells seen in thyroiditis can lead to a differential of papillary carcinoma. At the same time, it should also be kept in mind that papillary carcinoma can be associated with HT, so in suspicious cases a guided FNA can be done. Although FNA is highly sensitive in diagnosing HT, with a diagnostic accuracy rate of 92%, there is the likelihood to miss the diagnosis when cytology smears show evidence of hyperplasia as in case of Grave's disease or in cases where the colloid is abundant.  Another diagnostic pitfall is mistaking florid lymphocytic thyroiditis for low-grade lymphomas. In such cases, aspiration followed by flow cytometry of the aspirated specimen can resolve the problem by distinguishing between reactive lymphocytic population and neoplastic population, with the neoplastic monoclonal population showing kappa or lambda light chain restriction.
Ninety-five percent of the patients in our study showed an elevated ATPO value. Other studies have also shown the same percentage of patients with increase in ATPO values.  The patients presenting at an early stage have raised ATPO values, even before there is serological evidence of hormonal imbalance. Intrathyroidal immune destruction occurs much earlier to detectable serological evidence.  Three of our patients presented with decreased TSH values and elevated ATPO and ATG values and showed features of hyperthyroidism. One of the patients had grade 3 thyroiditis, one had grade 2 thyroiditis, and one had grade 1 thyroiditis. This phenomenon is seen in the active early stage of the disease wherein there is acute autoantibody mediated destruction of thyroid follicular cells.
Grading of thyroiditis was done according to the criteria given in [Table 2]. In our study, majority of patients presented with grade 1 disease. In the study by Bhatia et al., majority of the patients presented with grade 2 disease. However, in the study by Sood and Nigam, 40% of the patients had grade 3 thyroiditis. Though the present data indicate no significant statistical correlation between the cytological grades and the biochemical parameters, and we feel that this study is limited by the sample size. A larger sample size may be required to provide a definite result. In a study by Singh et al. that included a larger sample size of 150 cases, it was observed that the grading of thyroiditis and lymphocytic infiltration showed no correlation with the clinical severity of HT, while a high lymphoid:epithelial (L:E) ratio was strongly correlated with thyroid peroxidase positivity (P = 0.004).  However, in the study by Kumar et al. that studied the statistical correlation between the cytological grades of lymphocytic thyroiditis and the functional and antibody status and in the study by Bhatia et al. wherein the cytological grades were compared with clinical, biochemical, ultrasonographic, and radionuclide parameters no significant statistical correlation was observed.
| Conclusion|| |
To conclude we are of the opinion that HT should be diagnosed by a multidisciplinary approach wherein clinical, radiological, biochemical, cytological, and radionuclide parameters should be taken into consideration. However, in spite of the different diagnostic modalities available, demonstration of lymphocytic infiltration by FNAC still remains the gold standard. Though there is strong association of antithyroid antibodies, especially ATPO with HT, the present study and previous similar studies have failed to establish any significant correlation between the cytological grades and these parameters.
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Dr. K R Anila
Department of Pathology, Regional Cancer Centre, Thiruvananthapuram - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]