Volume 53
September–October 2009
Number 5
Cervical Lymphadenopathy Associated with Hashimoto’s Thyroiditis
An Analysis of 22 Cases by Fine Needle Aspiration Cytology

Nadir Paksoy, M.D., M.I.A.C., and Kadri Yazal, M.D.


Objective
To analyze the possible association between Hashimoto’s thyroiditis (HT) and cervical lymphadenopathy in cases diagnosed by fine needle aspiration cytology.
   
Study Design
Among the patients referred to our laboratory for ultrasound-guided fine needle aspiration cytology of thyroid nodules (USG-FNAC), cases of HT associated with cervical lymphadenopathy were evaluated.
   
Results
Between February 2001 and May 2007, HT was diagnosed in 94 (11%) of a total of 856 thyroid USG-FNAC cases. Among these cases, 22 (23%) were associated with single/multiple cervical lymphadenopathy. In all cases, FNAC of the lymph nodes was consistent with reactive lymphoid hyperplasia. Anti-TPO and anti-Tg antibody results were obtained in 14 of 22 cases with HT. Among these cases, 12 showed positive values.
   
Conclusion
Clinicians and cytopathologists who encounter thyroid nodules with cervical lymphadenopathy should also include the possibility of HT in the differential diagnosis. A literature search disclosed no report regarding the possible association between HT and cervical lymphadenopathy. Considering the limitations due to lack of immunocytochemical analysis of the thyroid and lymph node aspirates, our study should be taken as a preliminary one. (Acta Cytol 2009;53:491–496)

Keywords: aspiration biopsy, fine-needle; Hashimoto’s thyroiditis; lymphadenitis; lymphadenopathy; thyroid diseases.
    

Clinicians and cytopathologists who
encounter thyroid nodules with
cervical lymphadenopathy should
consider the possibility of HT in the
differential diagnosis.


Multinodular goiter is the most common nonneoplastic thyroid disease requiring fine needle aspiration cytology (FNAC); it is followed by thyroiditis, especially Hashimoto’s thyroiditis (HT).
    HT is an autoimmune disease characterized by hypothyroidism and asymmetric thyroid growth. Positive serologic results in antithyroid peroxidase antibody and/or antithyroglobulin antibody support the clinical diagnosis.1 The disease results in single or multiple nodules or nodulelike structures (pseudonodules) in the thyroid tissue. FNAC is used for the microscopic evaluation of these nodules.2,3
    We studied 22 cases of HT associated with cervical lymphadenopathy among patients referred to us for the ultrasound-guided fine needle aspiration cytodiagnosis of thyroid nodules (USG-FNAC). We also analyzed the possible association between HT and cervical lymphadenopathy.
   
Materials and Methods
Kocaeli is a province located east of Istanbul with a population of 1.5 million. The province is regarded as the industrial center of Turkey. Our cytopathology laboratory is a private practice located in the provincial center of Izmit. We apply FNAC in a clinical setting called the “Scandinavian model.” Patients requiring FNAC of the thyroid as well as other superficial sites are referred to the cytopathologist by clinicians. In a radiology center close to the cytopathology laboratory, FNAC is applied by a cytopathologist under ultrasound guidance by a radiologist. A 23-gauge needle with a 10-mL syringe attached to an aspirator is used.
    Bloody and cystic aspirates are transferred into 80% alcohol for the preparation of a cell block. Upon on-site inspection for material sufficiency, half of the remaining slides are fixed with methyl alcohol and stained with Diff-Quik, whereas the other half is fixed in ethyl alcohol and stained with Papanicolaou stain. Immunocytochemical (ICC) analysis was not carried out for either thyroid or lymph node aspirates due to the unavailability of immunologic facilities.
   
Results
Clinical Findings
During the 6.5-year period from February 1, 2001, to May 31, 2007, 856 thyroid USG-FNACs were carried out in our setting. Among 856 cases, 94 (11%) patients (8 male, 86 female) were diagnosed as having HT. The mean age of the female patients was 42.8 years (range, 17–68), whereas the mean age of males was 44.5 (range, 33–52). Twenty-two (23%) of 94 HT cases were associated with cervical lymphadenopathy.
    In 14 of the 22 cases, adenopathy had already been detected with previous USG investigations before the patients were referred to us. In the remaining 8 cases, adenopathy was found by our radiologist during the USG-FNAC procedure. The clinicopathologic data on the 22 cases are summarized in Table I.
  

   
Cytologic Findings
In all cases, the thyroid aspirates revealed the typical cytomorphologic features of HT: diffuse mature and mixed lymphoid population, epithelioid histiocytes, metaplasic Hürthle cells and macrophages were seen (Figure 1). Cytologic pictures of the lymph nodes were consistent with reactive hyperplasia. Aspirates were characterized by a polymorphic, mature lymphoid population; small lymphocytes; tingible-body macrophages; lymphohistiocytic aggregates; and eosinophils (Figure 2). A heterogeneous population of lymphoid cells, in which small lymphocytes predominated, was present on all of the slides. Cytology of the lymph nodes in all cases was suggestive of follicular hyperplasia rather than sinus histiocytosis.
   

   
   
   
Control Group
A similar number of cases (94) with nonneoplastic thyroid nodules (adenomatous nodules/benign colloidal nodules) were selected from our pathology database from May 31, 2007, to February 1, 2001, as the control group. Four patients had cervical lymphadenopathy. All of the nodules were single, measured 1 cm in diameter and were cytologically interpreted as reactive hyperplasia.
   
Follow-up
Twenty-two HT cases with cervical adenopathy were followed up during a period ranging from 9 months to 7 years depending on the date of the FNAC diagnosis. Follow-up was carried out by periodic contact with the patients and their physicians. At this writing we did not receive any feedback in terms of malignancy.
   
Literature Search
Literature screening was carried out by using Internet search engines as of July 2007. The keywords Hashimoto’s thyroiditis, lymphocytic thyroiditis, cervical lymphadenopathy and fine needle aspiration cytology were tried in various combinations. No other report regarding the possible association of HT with cervical lymphadenopathy was found.
   
Discussion
HT is an autoimmune inflammatory lesion of the thyroid. Therefore, it is evaluated under the title of autoimmune thyroiditis. In practice, HT is used synonymously with lymphocytic thyroiditis.
    The diagnostic spectrum of HT includes clinical symptoms, ultrasonographic appearance and positive serologic values as well as FNAC. HT can be associated with malignancy. Apart from the contribution to the differential diagnosis, FNAC may also aid in assessing the microscopic phase of the disease.3-5 
    The FNAC findings in the early phase of HT are that of focal lymphocytic thyroiditis. Therefore, they may be suggestive but not diagnostic. In late phase of HT, the FNAC diagnosis becomes difficult due to fibrosis.6-8
    Serologic tests may not give positive results in all HT cases. In a study of 50 HT cases, serologic tests revealed positive values in 25 (52%) of 48 patients. Although FNAC findings were compatible with HT, the serologic tests were negative in these cases.9
    There may be involvement of multiple organs in HT patients. Cases of HT associated with lymphocytic adrenalitis (Schmidt’s syndrome), lymphocytic pneumonia and autoimmune hepatitis have been reported.10-13
    Our literature search disclosed 4 reports of HT showing lymphadenopathies; however, the lymphadenitis in these cases was consistent with Kikuchi’s disease (KD).14-17 In 2 of these cases, connective tissue disease was also present.13,15 In our cases, none of the lymph node aspirates was in favor of KD. The FNAC findings of KD are well documented.18,19 Our cases revealed no debris or phagocytic histiocytes with sharply angulated nuclei, regarded as microscopic features in favor of KD.
    It is relatively easier to distinguish HT from large cell lymphoma on cytomorphologic grounds. However, it may be difficult to differentiate HT from low grade lymphoma. A report by Lerma et al20 states that in case of “any deviation from the characteristic heterogeneous cellular appearance of HT,” lymphoma should be suspected. Furthermore, ICC and/or flow cytometry may be required. There may be cases in which even flow cytometric assessment is insufficient. HT cases displaying monoclonality have been reported.21 In a study by Tani and Skoog,22 ICC was used in conjunction with cytomorphology to evaluate fine needle aspirates from 18 patients with nodular lymphoid infiltrates of the thyroid. Cytomorphology could not differentiate between an inflammatory and neoplastic lymphoid infiltrate in 2 cases. ICC showed monoclonality (neoplastic) in 1 case and polyclonality (inflammatory) in 1 case. In another report with 17 surgical cases of primary thyroid lymphoma, ICC analysis disclosed 3 cases to be maltoma that were preoperatively diagnosed as HT by FNAC.23
    A conclusive diagnosis of reactive lymphadenopathy requires immunologic backup (flow cytometry or cytospin), particularly for excluding low grade lymphomas. Due to lack of these facilities, we were unable to carry out the said methods, but we strictly adhered to the cytomorphologic criteria of nonspecific reactive hyperplasia on fine needle aspirates. Under conditions in which there is no access to immunophenotypic studies, the most reliable morphologic feature is heterogeneity of the lymphocytes.2,24 A heterogeneous population of lymphoid cells, a mixture of dispersed lymphoid cells in which small lymphocytes predominated, was present in all of our cases. In relation to the known statistically increased risk of malignancy in HT, especially in the nodular forms, the lymph nodes require routine assessment. A considerably long follow- up period showed no evidence of malignancy as of March 2008.
    The presence of cervical lymphadenopathy was not indicated by the clinician in 8 cases. Cervical lymphadenopathy was found by our radiologist at the time of USG-FNAC. This indicates the importance of application of FNAC under USG by or in the presence of a cytopathologist.25,26
    Based on the fact that HT is an autoimmune disease, it is also possible that the cervical lymphadenopathies are related to autoimmune reactions. The literature research disclosed no similar report showing the possible association between HT and cervical lymphadenopathy. Because of the limitations due to the unavailability of immunologic backing, our study should be taken as a preliminary one that may shed light on this matter. Clinicians and cytopathologists who encounter thyroid nodules with cervical lymphadenopathy should consider the possibility of HT in the differential diagnosis.
   
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From Paksoy’s Cytopathology Laboratory and Konrad Radiology Center, Izmit, Kocaeli, Turkey.

Dr. Paksoy is Cytopathologist, Paksoy’s Cytopathology  Laboratory.

Dr. Yazal is Radiologist, Konrad Radiology Center.

Address correspondence to: Nadir Paksoy, M.D., M.I.A.C., Sitopatoloji Lab, Hurriyet Cad, Safak Apt 125/17, 41300, Izmit, Kocaeli, Turkey (citographica@superonline.com).

Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

Received for publication March 13, 2008.

Accepted for publication May 26, 2008.




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