Background: There is little information regarding the natural course of hypoechoic thyroid lesions that are probable or possible thyroid lymphoma based on fine needle aspiration cytology (FNAC) results. Methods: Sixty-five patients who were diagnosed as probable or possible thyroid lymphoma by ultrasonography (US) and FNAC were investigated. Forty-three patients with strong suspicion underwent thyroid surgery for the diagnosis at our hospital, and 22 patients were followed up with periodic US examination. Thyroid lymphoma was definitely diagnosed in 41 out of 43 patients who underwent thyroid surgery, and such patients were defined as Group A. The outcomes of 22 patients who were followed up without an immediate therapy were analyzed. Their hypoechoic lesions decreased in size (n = 10) or disappeared (n = 2) in 12 of 22 patients, and such patients were defined as Group B. Patients in Group A and B were compared using the Kuma Hospital-US classification (USC), the diagnostic categories of the Bethesda System for Reporting Thyroid Cytopathology, and the κ/λ deviation of the immunoglobulin light chain in the FNAC specimens. Mann-Whitney U-test and chi-squared test (with Yate’s continuity correction) were used to compare the two groups. Results: The USC of < 3.5 [9/12 (75.0%) in Group B; 10/41 patients (24.4%) in Group A] and the κ/λ deviation ratio of < 3.40 [11/12 (91.7%) in Group B; 17/41 patients (41.5%) in Group A] were significantly more frequent (p < 0.01), and the FNAC of ‘benign’ or ‘atypia of undetermined significance or follicular lesion of undetermined significance (AUS)’ with a comment of possible lymphoma [9/12 (75.0%) in Group B; 12/41 patients (29.3%) in Group A] was significantly more frequent (p < 0.05) in Group B than Group A. Conclusions: Our study suggests that some hypoechoic thyroid lesions that are possible thyroid lymphoma based on US and FNAC might decrease in size or disappear during the careful observation. Keywords: Thyroid lymphoma, Hypoechoic thyroid lesion, Regression, Fine needle aspiration cytology, κ/λ deviation * Correspondence: firstname.lastname@example.org Department of Internal Medicine, Kuma Hospital, Centre for Excellence in Thyroid Cares, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nakao et al. Thyroid Research (2018) 11:8 Page 2 of 8 Background based on FNAC findings. We conducted the present Primary thyroid lymphoma is a rare cause of malignancy, study to (1) clarify the natural course of hypoechoic accounting for 2–5% of all thyroid malignancies and thyroid lesions that were possible thyroid lymphoma, < 2% of extranodal lymphomas [2, 3]. A rapidly enlarging and (2) identify clinical features that might be used to mass was the most common clinical manifestations in discriminate benign non-progressive lesions from those earlier series, but recently small lesions are found at the with progressive character. early stage . It is a potentially lethal disease, but often responds well to appropriate treatments . Thyroid lymphoma is not always diagnosed easily, especially in Methods its early phase, because most of the cases are associated Between April 2012 and July 2016, 136 patients were with Hashimoto’s thyroiditis. suspected of having thyroid lymphoma on US examin- Ultrasonography (US) of the thyroid is initially used for ation at Kuma Hospital, where approximately 15,000 the diagnosis of thyroid lymphoma. On US, lymphoma is new patients with thyroid diseases are evaluated annu- shown as hypoechoic lesions, but subacute thyroiditis, ally. US examinations were routinely performed by our focal chronic thyroiditis, some thyroid cancers, and meta- well-experienced operators. US was performed using an static thyroid cancer is also shown as hypoechoic lesions APLIO 500 TUS-A500 system (Toshiba Medical mimicking thyroid lymphoma. Based on US findings of Systems Co., Ltd., Otawara, Japan) with a PLT-805AT internal echo levels, borders, and posterior echoes, thyroid (Toshiba) or PLT-1005BT probe (Toshiba). Patients with lymphoma can be classified as the nodular, diffuse, or systemic lymphoma or previously diagnosed lymphoma mixed type . Although the nodular type often resembles were excluded. Of these 136 patients, 122 were diag- follicular tumor or adenomatous nodule and the mixed nosed as having probable or possible thyroid lymphoma type often resembles adenomatous goiter on US, these by FNAC (Fig. 1). The remaining 14 patients were ex- lesions can be often distinguished by an enhancement of cluded from the study, because they had other diagnoses posterior echoes. The diffuse type shows homogeneous based on FNAC findings (eight specimens were normal and hypoechoic internal echoes, but these findings are or benign, one anaplastic carcinoma of the thyroid, one also typical for severe chronic thyroiditis [6, 7]. subacute thyroiditis or thyroid papillary carcinoma, and Fine needle aspiration cytology (FNAC) is the next one metastatic renal cell carcinoma; the remaining three diagnostic strategy for thyroid lymphoma, but is challen- specimens were inadequate for diagnosis). Among the ging, particularly due to its histological similarities with 122 patients, 57 were excluded from the study, because mucosa-associated lymphoid tissue (MALT) lymphoma 56 were referred to other hospitals for the definitive and chronic thyroiditis [8, 9]. The flow cytometry with diagnosis and chemo radiotherapy, and one patient CD45 gating on the FNAC specimen can be used to dropped out from the follow-up study. Thus, the analyze the proportions of lymphocytic cells with κ and remaining 65 patients were investigated in this study. λ immunoglobulin light chains. The κ/λ deviation ratio Forty-three patients strongly suspected of having thyroid of the light chain assessment is an important criterion lymphoma underwent thyroid surgery at our hospital for for discriminating between polyclonal reactive processes the definite diagnosis and 22 patients with comments of such as chronic thyroiditis and monoclonal lymphomas. possible lymphoma on cytology were followed up with Strong deviation in the κ/λ ratio is regarded as suggest- periodic US examination for 1–41 (median 11.5) ive monoclonal growth of lymphocytes, thus indicating months. Whether surgery or follow-up examination was thyroid lymphoma . determined by each doctor in charge based on clinical Even with these modalities, a definite diagnosis is not and radiological findings, including the rapidity of the established easily. A surgical interventions is often needed enlargement of the thyroid mass, and the US and FNAC for the histopathological diagnosis, but it might be findings. Of 43 patients who underwent thyroid surgery unnecessary for the benign lesions. This is especially true at our hospital, 41 (95.3%) were diagnosed as definite for the small or moderate-size lesions. Needle biopsy is thyroid lymphoma, and the other two (4.7%) were usually useful for the diagnosis of diffuse large B-cell type diagnosed as chronic thyroiditis (Fig. 1). Among the 41 lymphoma, but is often insufficient in the case of MALT patients who were diagnosed as definite thyroid lymph- lymphoma. oma, 34 were diagnosed as MALT lymphoma and seven We have observed some hypoechoic lesions that were were diagnosed as diffuse large B-cell lymphoma. diagnosed as possible thyroid lymphoma based on the Whether the lesions of all 41 patients were limited to FNAC decrease in size or disappear during their clinical the thyroid was not known because all were referred to courses without definitive treatment. However, there is other hospitals to undergo further diagnostic examina- little information regarding the natural course of such tions, including the determination of the disease stage, hypoechoic lesions that were possible thyroid lymphoma and treatment. Nakao et al. Thyroid Research (2018) 11:8 Page 3 of 8 Suspicious of thyroid lymphoma by US (n=136) 14 patients excluded by FNAC* Probable or possible thyroid lymphoma by FNAC (n=122) Referred to other hospitals (n=56) Dropped out (n=1) Subjects of the present study (n=65) Follow-up examination Thyroid surgery (n=22) (n=43) Chronic thyroiditis (n=2) Thyroid lymphoma (n=41) Group A Decrease (n=10) No change (n=1) Increase (n=3) Drop out (n=6) Disappear (n=2) Group B *described in text. Group A: patients with definite thyroid lymphoma diagnosed pathologically. Group B: patients with hypoechoic lesions which decreased in diameter or disappeared. Fig. 1 Clinical flow and outcomes of patients with possible thyroid lymphoma based on US and FNAC Hypoechoic lesions of the periodically followed-up 22 during the follow-up examination. Other medications or patients were analyzed. The US examination was repeated supplementations, or dietary habit including iodine intake 1–3 month-interval at first and then 6 month-interval were not known in detail. When the maximum diameter when no deterioration was observed. None of 22 patients of a hypoechoic lesion increased by ≥3 mm, we defined were treated with steroids or immunosuppressive drugs the case as an “increase” of the hypoechoic lesion. When A1 B1 C1 B2 C2 A2 Fig. 2 Echograms of three representative patients whose hypoechoic lesions decreased or disappeared on careful follow-up examination. a A74-year- old woman with a nodular hypoechoic lesion at presentation (A1) that had markedly decreased in size one month later (A2) (case No. 9 in Table 2). b A 69-year-old woman with a severely hypoechoic lesion involving the both thyroid lobes (B1) that had almost disappeared 10 months later (B2), although the irregularity remained possibly due to underlying chronic thyroiditis (case No. 4 in Table 2). c A 53-year-old woman with a diffuse severely hypoechoic lesion involving the whole thyroid (C1) that had markedly decreased in size 27 months later (C2) (case No. 1 in Table 2) Nakao et al. Thyroid Research (2018) 11:8 Page 4 of 8 the maximum diameter of a hypoechoic lesion reduced by A and B. Mann-Whitney U-test and chi-squared test ≥3 mm, we defined the case as a “decrease.” When the (with Yate’s continuity correction) were used to compare hypoechoic lesions were not detected clearly at follow-up the two groups. examination, it was defined as “disappeared.” We estab- lished this parameter because, in our previous study, plus Results or minus 2 mm was recognized as an observation vari- Table 2 summarizes the clinical features of 16 patients who ation . In the present study, in some cases in which underwent follow-up US examinations of hypoechoic the entire thyroid volume was observed to have decreased, lesions that were diagnosed as possible thyroid lymphoma. the maximum diameter of the hypoechoic lesions was Thyroid function tests at presentation showed hypothyroid measured and analyzed. (n = 1), subclinical hypothyroid (n = 4) and euthyroid (n = Representative US images showing “decrease” and “dis- 11). Some patients were taking levothyroxine (LT4) before appearance” are shown in Fig. 2. Our hospital uses its own and during the follow-up examination. However, whether ultrasound classification system for the diagnosis of thy- LT4 supplementation was involved in the decrease or roid nodules, which consists of five US classes (USC) disappearance of the hypoechoic lesions is unclear, because based on the characteristics of thyroid nodules, such as a of the small number of the cases. All Group B patients were regular or irregular shape, solid or cystic content, the thyroglobulin antibody (TgAb)- and/or thyroid peroxidase presence or absence of microcalcifications, extraglandal antibody (TPOAb)-positive. As a result of FNAC, ‘atypia of invasion, and other factors. The classification consists of undetermined significance or follicular lesion of undeter- five classes from 1 to 5. Intermediate classes from class 2 mined significance (AUS)’ was diagnosed in eight, ‘suspi- to class 4 (designated as classes 2.5 and 3.5) are also used cious for ‘malignancy’ in two, ‘malignancy’ in one, and (Table 1). Some cases of lymphoma with diffuse or ‘benign’ in one patient. The pathological report of case 2 in mixed lesion are hardly classified according to USC, Table 2 said that it was probably benign; however, lymph- because this classification is mainly scored to thyroid nod- oma could not be completely excluded. On flow cytometry ules. However, in the present study, the US classification of the fine needle aspirations, the κ/λ ratio varied from 0.31 was applied to the hypoechoic lesions. The present study to 4.61. When κ/λ ratio was lower than 1.00, we converted was approved by the Institutional Review Board of Kuma κ/λ ratio to λ/κ ratio (deviation ratio) to discriminate be- Hospital and the Ethics Committee in Kuma Hospital. tween the polyclonal reactive process and the monoclonal The hypoechoic lesions in 22 patients who were followed reactive process that is characteristic to lymphomas. up with periodic US examination decreased in size (n =10), There were no significant differences in age, sex, thyroid disappeared (n = 2), showed no change (n =1) or increased function, TgAb, TPOAb, echo pattern of hypoechoic in size (n = 3). The remaining six patients dropped out from lesions, USC, BethSys, the diameter of hypoechoic lesions, the follow-up examination. Of the three patients whose κ/λ deviation ratio, LT4 supplementation or TSH between hypoechoic lesions increased in size, one patient was the patients whose hypoechoic lesions decreased in size or referred to another hospital and diagnosed as diffuse large disappeared and patients whose lesions were unchanged B-cell lymphoma; the other two patients were carefully or increased in size. followed up without further progression (Fig. 1). There were no significant differences in patient age, Forty-one patients with histopathologically diagnosed sex, or the diameter of the hypoechoic lesions between thyroid lymphoma were defined as Group A, and 12 Groups A and B (Mann-Whitney U-test) (Table 3). The patients whose hypoechoic lesions decreased in diameter USC and the κ/λ deviation ratio were significantly lower or disappeared as defined Group B (Fig. 1). Their clinical in Group B than Group A (p < 0.001 and p < 0.02, features, the diameter of hypoechoic lesions, US features respectively). The USC of < 3.5 [9/12 (75.0%) in Group at the first presentation, and the diagnostic categories of B; 10/41 patients (24.4%) in Group A] was significantly the Bethesda System for Reporting Thyroid Cytopathol- more frequent (p < 0.01), and the FNAC finding of ‘be- ogy (BethSys categories) were compared between Group nign’ or ‘AUS’ [9/12 (75.0%) in Group B; 12/41 patients Table 1 Ultrasonographic classification for thyroid nodule at Kuma Hospital Class Description 1 Round or anechoic lesion. 2 Regular-shaped nodule with cystic change. The echo level of solid lesion is similar to that of normal thyroid. 3 Solid and regular-shaped nodule. Internal echo is homogeneous, or may have strong echoes internally or at the capsule. 4 Solid and irregular-shaped nodule. Internal echo is usually low and may have fine strong echogenic spots. 5 Solid and irregular-shaped nodule with extrathyroid extension. Intermediate classes from class 2 to class 5 (designated as classes 2.5,3.5 and 4.5) are also used Nakao et al. Thyroid Research (2018) 11:8 Page 5 of 8 Table 2 Clinical features of 16 patients who underwent follow-up US examinations of hypoechoic lesions that were diagnosed as possible thyroid lymphoma Case Age Sex Thyroid TgAb TPOAb Echo pattern US BethSys Duration of Before After (mm) κ/λ LT4 supplementation TSH during Outcome function (IU/mL) (IU/mL) of hypoechoic class follow-up (mm) deviation (μg/day) follow-up lesions (months) ratio 1 53 F subclinical 4000≦ 535 diffuse 3 AUS 27 61 47 1.21 75 normal decrease hypothyroid (with LT4 50 μg/day) 2 62 F hypothyroid 4000≦ 600≦ diffuse 3.5 benign 30 120 80 1.50 112.5 suppressed decrease 3 66 F euthyroid 28 89 nodular 3.5 AUS 12 25 11 4.61 50 normal decrease 4 69 F euthyroid 120.7 600≦ nodular 3 AUS 10 37 disappearance 3.14 – normal disappearance 5 70 M euthyroid 54 118 nodular 3 AUS 37 15 12 1.84 – normal decrease 6 71 M subclinical 1171 – nodular 3 malignancy 6 37 23 3.20 50 normal decrease hypothyroid 7 72 F euthyroid 906 – nodular 2.5 Suspicious for malignancy 3 27 14 2.90 50 normal decrease 8 74 F euthyroid 512.9 151 nodular 3 AUS 41 12 disappearance 2.75 – normal disappearance 9 74 F euthyroid 688.8 16 nodular 3 Suspicious for malignancy 1 105 25 1.72 – normal decrease 10 74 F euthyroid 121.8 – nodular 3 AUS 7 16 9 2.06 75 suppressed decrease 11 77 F subclinical 1402 – diffuse 3 AUS 25 46 40 1.53 50 normal decrease hypothyroid 12 83 F euthyroid 89.9 – nodular 3.5 AUS 6 23 19 3.21 – normal decrease 13 66 F euthyroid 235.5 – nodular 4 AUS 22 22 22 0.86 75 suppressed no change 14 46 F euthyroid 609.6 – nodular 3 Suspicious for malignancy 7 22 30 –– normal increase 15 87 M euthyroid 750.4 ≦16 nodular 3 Suspicious for malignancy 6 19 23 4.09 – normal increase 16 94 F subclinical 586.3 26.5 diffuse 3 Suspicious for malignancy 11 65 160 1.81 62.5 normal increase hypothyroid The normal range of TgAb is ≤39.9 U/mL; TPOAb: ≤27.9 U/mL. –: TPOAb not done or no levothyroxine (LT4) supplementation Intermediate US classes from class 2 to class 4 (designated as classes 2.5 and 3.5) are also used Thyroid function at the first examination and diagnosis as possible thyroid lymphoma by FNAC The Bethesda System for Reporting Thyroid Cytopathology The κ/λ deviation ratio was calculated by λ/κ ratio when the κ/λ ratio was < 1.00 Atypia of undetermined significance or follicular lesion of undetermined significance Lymphoma cannot be denied Nakao et al. Thyroid Research (2018) 11:8 Page 6 of 8 Table 3 Comparison of clinical features of Group A and B Group A (n = 41) Group B (n = 12) p-value Age (year) 67 (48–91) 72 (53–83) 0.35 Sex (Male, number) 11 2 0.48 Diameter of hypoechoic lesions (mm) 35 (16–75) 38 (12–120) 0.51 Group A is the patients with thyroid lymphoma diagnosed histopathologically following thyroid surgery. Group B is the patients whose hypoechoic lesions decreased or disappeared. Data are median and (ranges). The p-values were calculated by Mann-Whitney U-test (29.3%) in Group A] was significantly more frequent (p cytotoxic T-cell origin regressed spontaneously . Al- < 0.05) in Group B than Group A (Tables 4 and 5). though its cause remains unknown, it may be attributable Lastly, the κ/λ deviation ratio of the immunoglobulin to an association of acute inflammation [17, 18], and (Ig) light chain in the FNAC specimens of < 3.40 [11/12 immune mechanisms such as those involving T-helper cells (91.7%) in Group B; 17/41 patients (41.5%) in Group A] or natural killer cells of the peripheral blood . was significantly more frequent in Group B than Group However, to our best knowledge, there has been no A(p < 0.01) (Table 6). report that the natural course of hypoechoic lesions sus- pected of being possible thyroid lymphoma was studied Discussion extensively. With the combination of US, FNAC, and The characteristics and natural course of hypoechoic CD gating analysis for κ/λ deviation, candidate for the lesions that were diagnosed as possible thyroid lymph- surgery could be accurately selected in 41 out of 43 oma based on the FNAC findings were investigated. patients (95%) as demonstrated in Group A. However, Careful US examinations were repeatedly performed in the management of not strongly suggestive of lymphoma 22 of 65 patients, and hypoechoic lesions decreased in may be controversial. In the present study, the hypoe- diameter in 10 patients (10 of the 22; 45.5% or 10 of 65 choic lesion decreased in size in 10, and disappeared in patients; 15.4%), and disappeared in two patients (two of two out of 22 patients, suggesting the careful observa- 22; 9.1% or two of 65 patients; 3.1%). tion for such lesions. The USC and the κ/λ deviation ratio were significantly The limitation of the present study concerns the retro- lower in Group B than Group A, and the FNAC finding spective analysis that may eliminate the ability to obtain the of ‘benign’ or ‘AUS’ was significantly more frequent in strong conclusions. Selection of open surgery or careful ob- Group B than Group A. Although thyroid lymphoma servation depends on various factors including the results typically presents with a rapidly enlarging neck mass of FNAC and patients’ previous courses. Therefore, the leading to compressive symptoms , some hypoechoic proper diagnostic rate of Group A was higher than in that lesions diagnosed as possible thyroid lymphoma might of Group B, and the selection bias might cause the differ- regress in their natural courses in the present study. ence of the course of the two groups. The nature of the Several studies have demonstrated that Helicobacter hypoechoic lesions that regressed during the follow-up pylori infection is associated with low-grade gastric MALT examination is unclear in the present study, because open lymphoma, and that the eradication of Helicobacter pylori biopsies were not performed in these patients. Some could can cause histological regression of the lymphoma [13, 14]. be actually low-grade thyroid lymphoma, but others could Uohashi et al. reported that a hypoechoic lesion in the right be focal or regional lymphocytic thyroiditis, atypical lobe disappeared spontaneously after being diagnosed subacute thyroiditis, or other etiology-unknown lesion(s). pathologically as non-Hodgkin’s lymphoma following a Further prospective studies including histopathology and contralateral lobe resection, and suggested spontaneous factor(s) involved in the regression or progression of the regression of acute inflammation . Okamoto et al. re- ported a patient whose primary thyroid lymphoma of Table 5 Comparisons of the diagnostic categories of the Bethesda System for Reporting Thyroid Cytopathology between Table 4 Comparisons of US classification between the Group A the Group A (n = 41) and Group B (n = 12) (n = 41) and Group B (n = 12) Diagnostic categories Group A Group B US class Group A Group B Benign 1 1 2.5 1 1 AUS 11 8 39 8 Suspicious for malignancy 22 2 3.5 9 3 Malignant 7 1 421 0 P < 0.02 P < 0.01 US: ultrasound. AUS: atypia of undetermined significance or follicular lesion of Classes 2.5 and 3.5 designate intermediate classes between 2 &3 and 3 & undetermined significance 4, respectively Benign: benign, but with the comment that lymphoma cannot be denied Nakao et al. Thyroid Research (2018) 11:8 Page 7 of 8 Table 6 Comparisons of Groups A and B regarding the κ/λ Consent for publication The patient has provided their consent for the contents of this report to be deviation ratio of Ig light chain published. κ/λ deviation ratio Group A Group B Total ≥3.40 24 1 25 Competing interests The authors declare that they have no competing interests. < 3.40 17 11 28 Total 41 12 53 Publisher’sNote The κ/λ deviation ratio of < 3.40 was significantly more frequent in Group B Springer Nature remains neutral with regard to jurisdictional claims in compared to Group A (p < 0.01, chi-square test (with Yate’s continuity published maps and institutional affiliations. correction)). When the κ/λ deviation ratio was lower than 1.00, we converted it to the λ/κ ratio (deviation ratio) Author details Department of Internal Medicine, Kuma Hospital, Centre for Excellence in Thyroid Cares, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan. lesions are needed to investigate the true nature of such Department of Diagnostic Pathology and Cytology, Kuma Hospital, Centre lesions, and to clarify the best method of managing such for Excellence in Thyroid Cares, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe patients. 650-0011, Japan. Department of Surgery, Kuma Hospital, Centre for Excellence in Thyroid Care, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe Hypoechoic lesions suspected of having possible lymph- 650-0011, Japan. oma decreased in size or disappeared in 12 out of 22 pa- tients (55%), and such a regression should be emphasized Received: 17 February 2018 Accepted: 22 May 2018 in the present study. 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Published: May 30, 2018