Annals of Diagnostic Pathology 19 (2015) 175–179

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Annals of Diagnostic Pathology

Cytologic-Pathologic Correlation

Cytomorphologic features and ultrasonographic characteristics of thyroid nodules with Hurthle cells Dilek Tuzun, MD a,⁎, Reyhan Ersoy b, Aylin Kilic Yazgan, MD c, Gulten Kiyak d, Samet Yalcin e, Bekir Cakir b a

Department of Endocrinology and Metabolism, Ankara Atatürk Education and Research Hospital, Ankara, Turkey Department of Endocrinology and Metabolism, Yildirim Beyazit University, Ankara, Turkey Department of Pathology, Ankara Atatürk Education and Research Hospital, Ankara, Turkey d Department of General Surgery, Ankara Atatürk Education and Research Hospital, Ankara, Turkey e Department of General Surgery, Yildirim Beyazit University, Ankara, Turkey b c

a r t i c l e

i n f o

Keywords: Thyroid nodule Hurthle cell Ultrasonography Cytomorphology

a b s t r a c t This study was designed to evaluate the ultrasonographic and histopathologic features of nodules composed predominantly of Hurthle cells detected during cytological examination. Fifty-seven patients with thyroid nodules composed predominantly of Hurthle cells on fine needle aspiration cytology were retrospectively analyzed. Patients were evaluated by thyroid ultrasonography (US), and biopsy samples taken by US-guided fine needle aspiration cytology were assessed histopathologically. There were 57 patients and 57 nodules with Hurthle cells in cytological examination; 49 (86%) were classified as Bethesda 1, and 8 (14%) were classified as Bethesda 3. Histopathologically, 45 (78.9%) nodules were benign and 12 (21.1%) were malignant. Nuclear groove, transgressing blood vessel, and absence of colloid were observed with a higher frequency in malignant nodules compared to benign nodules (P b .05). There were no specific morphological features (nodule echogenity, presence of microcalsification, presence of cystic areas, absence of halo, margin irregularity, and increased blood flow) predicting malignancy in the US evaluation of nodules including Hurthle cells. Nuclear groove, transgressing blood vessel, and absence of colloid on cytomorphological evaluation are indicative of malignancy in nodules containing Hurthle cells. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Hurthle cells are characterized cytologically as large polygonal cells with abundant eosinophilic, granular cytoplasm and a large hyperchromatic nucleus with a prominent nucleolus [1]. Hurthle cells are present in a variety of nonneoplastic conditions involving the thyroid and are not specific for any disease process [2,3]. Thyroid nodules containing Hurthle cells are present in patients with a wide range of pathologic entities, including Hashimoto thyroiditis (HT), Hurthle cell adenomas (HCAs), Hurthle cell carcinomas (HCC), oncocytic variant of papillary carcinoma, and medullary carcinoma [4,5]. Many morphologic studies have attempted to identify cytomorphologic features that distinguish benign Hurthle cell lesions (BHCLs) from Hurthle cell neoplasms (HCNs). Among the features that distinguish BHCL from HCN are nonmacrofollicular architecture, absence of colloid, absence of chronic inflammation, presence of transgressing blood vessels (TBVs), predominantly Hurthle cells, small cell dysplasia, large cell dysplasia, nuclear crowding, and marked dyshesion [2,3,6–8]. This study was designed to assess the ultrasonographic, cytologic results and histopathologic features of ⁎ Corresponding author at: Ankara Atatürk Research and Training Hospital, Department of Endocrinology and Metabolism, Bilkent Yolu, No: 2. Tel.: +90 312 2912525x4859; fax: +90 312 2912705. E-mail address: [email protected] (D. Tuzun). http://dx.doi.org/10.1016/j.anndiagpath.2015.03.002 1092-9134/© 2015 Elsevier Inc. All rights reserved.

thyroid nodules containing Hurthle cells in patients who underwent surgery for various reasons.

2. Materials and methods 2.1. Study protocol This study was a retrospective evaluation of 57 patients found by fine needle aspiration cytology to have thyroid nodules consisting predominantly of Hurthle cells and who underwent surgery between June 2009 and June 2010. Medical history was obtained, and all patients underwent thyroid examinations. Concentrations of thyroidstimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and the thyroid autoantibodies thyroid peroxidase antibody (anti-TPO) and anti-thyroglobulin antibody (anti-TgAb) were measured. Thyroid ultrasonography (US) was performed by an experienced specialist using the same US machine. Fine needle aspiration biopsy (FNAB) was performed by an experienced specialist in thyroid nodules and evaluated by a cytopathologist. Patients were reevaluated by US and Doppler US and discussed by a multidisciplinary team consisting of endocrinologists, general surgeons, and pathologists; this evaluation guided surgeons in determining the surgical approach in patients who required surgery.

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Indications for surgery in patients with nodules containing Hurthle cells included large nodule diameter, compression symptoms, and increased nodule diameter over time. Nodules showing evidence of HCN were removed surgically because of a high suspicion of malignancy. Fifty-seven patients underwent total thyroidectomy in our hospital, with all operations performed by the same surgical team. The resected nodules were evaluated histopathologically by the same cytopathologist who evaluated the FNAB specimens. The study protocol was approved by the local ethical committee (Ankara Ataturk Research and Education Hospital Local Ethical Committee Decision: Date: 01.06.2009; Decision Number: 10.06.2009). 2.2. Exclusion criteria Patients younger than 18 years and those with a previous history of thyroid surgery or percutaneous invasive procedure for thyroid nodule or radiotherapy of the head and neck region were excluded from the study. Also excluded were patients with cardiac or pulmonary disease that could complicate surgery; those with pure cystic nodules, hemorrhagic nodules, multinodular coalescent nodules of undetermined sizes, anaplastic carcinoma, and Riedel thyroiditis; and patients with extensive cervical metastasis that may need radical neck dissection. Patients who refused surgery were also excluded. 2.3. Laboratory examination Serum TSH, fT3, fT4, anti-TPOAb, and anti-TgAb concentrations were measured by chemiluminescence methods using commercial kits (Chemiluminescent Microparticle Immunoassay, CIMA®) with an Abbott Architech machine. Reference ranges for TSH, fT3, fT4, Tg, anti-TPOAb and anti-TgAb were 0.35 to 4.94 IU/mL, b10 IU/mL, 1.57 to 4.71 pg/mL, 0.61 to 1.12 ng/dL, 0 to 55 ng/mL, and b30 IU/mL, respectively. 2.4. Ultrasonography Esaote color Doppler US (MAG Technology Co, Ltd. Model: 796FDII Yung-ho City, Taipei; Taiwan) and a superficial probe (Model No: LA523 13-4, 5.5-12.5 MHz) were used for standard US. Standard US was utilized to evaluate nodule localization, diameter (mm), volume, halo, echogenicity, marginal regularity, and type of calcification and vascularization pattern (stage 1, absence of blood flow; stage 2, peripheral vascularization; stage 3, intranodular vascularization; stage 4, marked intranodular vascularization).

Table 1 The Bethesda system for reporting thyroid cytopathology: recommended diagnostic categories I. Nondiagnostic or unsatisfactory Cyst fluid only Virtually acellular specimen Other (obscuring blood, clotting artifact, etc.) II. Benign Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodul,etc. Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context Consistent with granulomatous (subacute) thyroiditis Other III. Atypia of undetermined significance or follicular lesion of undetermined significance IV. Follicular neoplasm or suspicious for a follicular neoplasm Specify if Hurthle cell (oncocytic) type V. Suspicious for malignancy Suspicious for papillary carcinoma Suspicious for medullary carcinoma Suspicious for metastatic carcinoma Suspicious for lymphoma Other VI. Malignant Papillary thyroid carcinoma Poorly differentiated carcinoma Medullary thyroid carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Carcinoma with mixed features (specify) Metastatic carcinoma Non-Hodgkin lymphoma Other

specimens were examined macroscopically by the cytopathologist, photographs were taken and all the specimens were scored using standard methods, thus enabling previous US and cytology data to be compared with the histopathologic findings, as determined using the 2004 WHO classification [11]. 2.7. Statistical analysis All statistical analyses were performed with SPSS 18.0 (SPSS Inc., Il., USA) statistical soft-ware. Qualitative data were reported as frequencies and compared using χ2 tests; quantitative data were reported as mean ± SD and compared using unpaired Student t test or Mann–Whitney U tests. P ≤ .05 was defined as statistically significant.

2.5. US guided FNAB

3. Results

FNAB was performed under US guidance using a General Electric Logiq pro 200 (Model number: 2270968; GE Healthcare Korea, Seongnam-SI, Gyeon GGI-DO, Korea) and a 5.5 to 7.5 MHz probe.

Fifty-seven nodules in 57 patients were retrospectively evaluated. Mean age was 46.12 ± 11.69 years (range, 19-73 years). Of the 57 patients, 52 (91.2%) were female and 5 (8.8%) were male. All patients were euthyroid at the time of investigation, with a mean serum concentration of TSH of 1.51 ± 1.01 μIU/mL. Twenty-four patients (42.1%) were positive for anti-TPOAb and/or anti-TgAb. According to the Bethesda classification of cytology, 49 (86%) of the 57 nodules were Bethesda 2 and 8 (14%) were Bethesda 4. These two subgroups were similar in age, sex distribution, thyroid function test results, nodule volume, sonographic features and nodule vascularization pattern. Of the 57 nodules, 12 (21.1%) were diagnosed on final histopathology as malignant and 45 (78.9%) as benign. These two subgroups were also similar in age, sex distribution and thyroid function test results, as well as in nodule volume, gray-scale US features, and vascularization pattern. Evaluation of cytological features showed that cellularity, the presence of Hurthle cells, and large cell dysplasia were significantly more frequent in the Bethesda 4 than in the Bethesda 2 group (P b .05; Table 2). Moreover, nuclear groove, TBV, and absence of colloid were significantly more frequent in malignant than in benign nodules (P b .05; Table 3) (Figs. 1, 2, 3). Histopathological examination of the 12

2.6. Cytological and histopathological examination Materials obtained by US guided FNAB were air dried, stained with May-Grünwald-Giemsa stain and classified according to the Bethesda system [9] (Table 1). The 14 cytomorphologic features used to distinguish BHCL from HCN were cellularity, background colloid, macrophage count, lymphocyte count, TBV, capillaries, nuclear crowding, Hurthle cells, cellular dyshesion, nuclear enlargement, small cell dysplasia, large cell dysplasia, macronucleoli, and binuclear Hurthle cells. Transgressing blood vessels were defined as capillaries passing through clusters of Hurthle cells [10]. The US-determined location of the nodule or nodules in the thyroid tissue was shown to the surgeon using a simple drawing. The surgical team marked the nodule or nodules with a surgical suture before sending the specimen for histopathological examination, so that the suspicious area could be examined with particular interest. Thyroidectomy

D. Tuzun et al. / Annals of Diagnostic Pathology 19 (2015) 175–179 Table 2 Cytomorphological features of Bethesda 2 and Bethesda 4 nodules

Cellularity %

Colloid %

Macrophage %

Lymphoid %

TBV % Capillary % Dyshesion %

Hurthle cell %

Binuclear Hurthle % Nuclear groove % Macronucleolus % Nuclear enlargement %

Small cell dysplasia %

Large cell dysplasia %

Mild Moderate Excessive Absent Scanty Moderate Abundant Absent Scanty Moderate Abundant Absent Scanty Moderate Abundant Absent Present Absent Present Absent Less than 10% 10-50% More than 50% Less than 10% 10-50% 50-90% More than 90% Absent Present Absent Present Absent Present Absent Less than 10% 10-50% More than 50% Absent Less than 10% 10-50% More than 50% Absent Less than 10% 10-50% More than 50%

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Table 3 Cytomorphological features of benign and malignant thyroid lesions

Bethesda 2 (n = 49)

Bethesda 4 (n = 8)

P

59.2 36.7 4.1 18.4 34.7 38.8 8.2 59.2 32.7 6.1 2 24.5 53.1 16.3 6.1 91.8 8.2 61.2 38.8 67.3 22.4 6.1 4.1 36.7 32.7 20.4 10.2 85.7 14.3 73.5 26.5 87.8 12.2 32.7 30.6 14.3 22.4 85.7 8.2 4.1 2 65.3 14.3 16.3 4.1

25 50 25 25 37.5 25 12.5 75 25 0 0 50 50 0 0 75 25 50 50 50 12.5 12.5 25 0 0 62.5 37.5 62.5 37.5 75 25 62.5 37.5 0 50 12.5 37.5 50 25 25 0 25 62.5 12.5 0

.048

Cellularity %

.879

Colloid %

.787

Macrophage %

.334

Lymphoid %

.150

TBV %

.549

Capillary %

.149

Dyshesion %

.003

Hurthle cell %

.109

Binuclear Hurthle %

.927

Nuclear groove %

.069

Macronucleolus %

.257

Nuclear enlargement %

.06

Small cell dysplasia %

.020

Large cell dysplasia %

malignant nodules showed that 4 were papillary thyroid carcinoma (PTC), 3 were HCC, 2 were a follicular variant of PTC, 2 were follicular thyroid carcinomas, and 1 was a solid trabecular variant of PTC.

mild moderate Excessive Absent Scanty Moderate Abundant Absent Scanty Moderate Abundant Absent Scanty Moderate Abundant Absent Present Absent Present Absent Less than 10% 10-50% More than 50% Less than 10% 10-50% 50-90% More than 90% Absent Present Absent Present Absent Present Absent Less than 10% 10-50% More than 50% Absent Less than 10% 10-50% More than 50% Absent Less than 10% 10-50% More than 50%

Benign (n = 45)

Malign (n = 12)

P

57.8 35.16 6.7 15.6 28.9 44.4 11.1 53.,3 40 4.4 2.2 31.1 51.1 13.3 4.4 95.6 4.4 55.6 44.4 68.9 22.2 4.4 4.4 35.16 28.9 26.7 8.9 86.7 13.3 80 20 86.7 13.3 31.1 33.3 13.3 22.2 84.4 8.9 4.4 2.2 62.2 22.2 13.3 2.2

41.7 50 8.3 33.3 58.3 8.3 0 91.7 0 8.3 0 16.7 58.3 16.7 8.3 66.7 33.3 75 25 50 16.7 16.7 16.7 16.7 25 25 33.3 66.7 33.3 50 50 75 25 16.7 33.3 16.7 33.3 66.7 16.7 16.7 0 50 16.7 25 8.3

.606

.055

.766

.04 .223 .196

.160

.136 .036 .325 .740

.362

.532

from nonneoplastic lesions [6,21,22]. Alaeden et al [6] examined 622 nodules in their study. FNAB specimens were evaluated for specific cytologic features including overall cellularity, Hurthle cellularity, atypia,

4. Discussion Hurthle cells are thyroglobulin producing polygonal epithelial cells characterized cytologically as large cells with abundant eosinophilic, granular cytoplasm and a large hyperchromatic nucleus with a prominent nucleolus. These cells are present in both benign and malignant thyroid lesions and can cause difficulties in histopathological evaluation [11–20]. Hashimoto thyroiditis can be found at one end of the spectrum; whereas HCA, HCC, and oncocytic variants of papillary and medullary carcinomas can be found at the other end of the spectrum [4,5,11]. This study was designed to evaluate the US, cytologic, and histopathologic characteristics of nodules containing Hurthle cells in patients who underwent thyroid surgery for various reasons. We found that large cell dysplasia, lack of cellularity, and Hurthle cell rich pattern were significantly more frequent in HCNs than in benign lesions. The absence of colloid and macrophages, and the presence of TBV and nuclear groove, were significantly more common in malignant than in benign lesions. Several studies of the cytological evaluation of nodules with Hurthle cells have reported that no specific features can distinguish neoplastic

.035

Fig. 1. May Grunwald Giemsa, nuclear groove. Original magnification ×40.

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Fig. 2. May Grunwald Giemsa, transgressing vessels. Original magnification ×20.

colloid, lymphocytes, and/or histocytes. Of 45 patients suspected of having HCNs, 17 (38%) were found to have nonneoplastic disease and 28 (62%) had neoplastic disease. Twenty-one (47%) patients had HCA, 12 (27%) had adenomatous hyperplasia, and 5 (11%) had thyroiditis. Of the seven (16%) patients with malignant disease, 3 had HCC, 3 had an oxyphilic variant of papillary carcinoma, and 1 had a 1.5-cm papillary carcinoma with diffuse HT. These findings indicated that the presence or absence of a specific clinical or cytologic feature could not unambiguously exclude either HCA or carcinoma [6]. Elliot et al [2] performed a morphologic study to distinguish BHCL from HCN in 139 patients. Fourteen cytologic features were evaluated, including overall cellularity, cytoarchitecture, percentage of Hurthle cells, percentage of single cells, percentage of follicular cells observed as naked Hurthle cell nuclei, background colloid, chronic inflammation, cystic change, TBV, intracytoplasmic lumina, presence of multinucleated Hurthle cells, nucleus to cytoplasm ratio, nuclear pleomorphism/atypia, and nucleolar prominence. Six of these features were found to be statistically significant in identifying HCN. Moreover, the following four features, when found in combination, were found to be highly predictive of HCN: nonmacrofollicular architecture, absence of colloid, absence of inflammation, and presence of TBV [2]. MuddeGowda et al [7] examined several cytomorphologic features in FNAB samples from 233 patients: cellularity, colloid content, nuclear pleomorphism, hemorrhage, Hurthle cells, macrophages and lymphocytes. Of these 233 patients, 212 had benign lesions, including 138 with nodular colloid goiter, 15 with adenomatoid nodule, 17 with HT,

10 with HCA and 32 with follicular adenoma. The remaining 21 patients had malignant lesions, including 17 with papillary thyroid carcinoma, 3 with medullary carcinoma, and 1 with anaplastic carcinoma. Most aspirates of neoplasms had excess cellularity with a microfollicle-rich pattern, scanty colloid, mild nuclear features, and abundant hemorrhage. The malignant lesions had moderate to excess cellularity with monotonous crowding, absence of colloid, moderate to high nuclear features, and excessive hemorrhage [7]. According to Renshaw [3] all HCC could be identified using a total of five criteria: predominantly Hurthle cells and scant colloid and at least one of either small cell dysplasia, large cell dysplasia, crowding, and dyshesion. Wu et al [8] evaluated 35 FNAB specimens from patients diagnosed with Hurthle cell lesions or neoplasms divided these specimens histologically as HCC (n = 12), HCA (n = 14), and BHCL (n = 9). Eleven features were evaluated in each: lesion size; presence or absence of colloid, lymphocytes, and TBV; percentage of nuclear enlargement; small or large cell dysplasia; nuclear crowding; cellular dyshesion; and patient age and gender. Small cell dysplasia, large cell dysplasia, nuclear crowding, and cellular dyshesion were significantly more frequent in HCC than in benign lesions (HCA and BHCL), whereas the presence of colloid and lymphocytes was more frequent in benign lesions. Nuclear enlargement and large tumor size were significantly more common in neoplasms than BHCL. Our study also evaluated the US characteristics of thyroid nodules containing Hurthle cells. We found that no specific morphological features predicted malignancy, including nodule echogenicity, presence of microcalcification, presence of cystic areas, absence of halo, margin irregularity, and increased blood flow. Few reports have described the US features of nodules with Hurthle cells detected in FNAB. HCN showed a spectrum of sonographic appearances, from predominantly hypoechoic to hyperechoic, with some of these lesions containing cystic components [11]. We also found that the echogenicity of nodules varied considerably. Moreover, malignant and benign nodules did not differ in other gray scale morphological features. In our study, 12 of 57 nodules were malignant. Four of these nodules were PTC, 2 were PTC-follicular variant, 1 was PTC solid trabecular variant, 2 were follicular thyroid carcinomas, and 3 were HCC. The incidence and rates of malignancy of HCN in various institutions were found to be highly variable, with the rate of HCC ranging from 5% to 35% [15,16,23–25]. Few institutions have extensive experience in following-up patients with Hurthle cell predominant thyroid nodules, as shown by FNAB. Although total thyroidectomy has been recommended in patients with nuclear atypia detected in HCNs [25], cellular atypia is not a criteria distinguishing malignant from benign nodules. Cytologic atypia has been observed in adenomatous hyperplasia as well as in thyroiditis and HCA [23]. Thompson et al suggested that all HCN may be potentially malignant, therefore all such tumors required resection [26]. According to Alaedeen et al [6], thyroidectomy has been recommended for all patients with thyroid nodules and a predominance of Hurthle cells in FNAB specimens. That study recommended thyroid lobectomy and isthmectomy for these patients, with complete thyroidectomy reserved for patients with a final pathologic diagnosis of carcinoma, because carcinoma was diagnosed in only 16% of their patients with nodular thyroid disease and a predominance of Hurthle cells on FNAB specimen [6]. However, Mcleod et al [27] reported that treatments of HCN were controversial and there was no significant correlation between clinical behavior of the tumor and its microscopic. In conclusion, nuclear groove, present TBV and absence of colloid in cytomorphological evaluation seem to be the features that support malignancy in nodules including Hurthle cells cytologically. Since malignancy rate in our patient group was 21.1%, we think total or near total thyroidectomy should be preferred in nodules with Hurthle cells in cytological examination. Conflict of interest

Fig. 3. May Grunwald Giemsa, absence of colloid. Original magnification ×10.

The authors declare that they have no conflicts of interest.

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