Kamile Gul

The Association Between Thyroid Carcinoma and Hashimoto's Thyroiditis: The Ultrasonographic and Histopathologic Characteristics of Malignant Nodules

BACKGROUND Some but not all reports, particularly those of a retrospective nature, have noted an increased risk of carcinoma in thyroid nodules in patients with Hashimotos thyroiditis (HT). Thyroid cancer (TC) in patients with HT, however, have been reported to have a better prognosis. In the presence of HT, the ultrasonography (US) appearance of the thyroid gland might vary greatly, making it more difficult to differentiate between benign and malignant nodules. The aim of this study was to determine if there is an association between TC and HT and to determine if the US and histopathologic characteristics of malignant nodules in patients with and without HT are similar. METHODS Six hundred thirteen patients who underwent total thyroidectomy between 2005 and 2008 for nodular goiter were included in this study. The preoperative US characteristics and postoperative histopathologic features in patients with and without HT were compared. The diagnosis of HT was based on histopathologic features. RESULTS Ninety-two patients had HT. The prevalence of TC in the HT patients was 45.7%. In contrast, it was 29% in patients without HT (p = 0.001). The prevalence of HT in the patients with TC was 21.8% and in patients without TC was 11.9% (p = 0.001). The rate of incidental TC, defined as TC identified during surgery or following histopathologic examination of permanent sections despite preoperative benign cytology results, was higher in patients with HT (33.3%) than in those without (13.0%) HT (p = 0.004). The US characteristics of papillary thyroid carcinoma, which included number of nodules, echogenity, echoic texture, microcalcifications, macrocalcifications, halo sign, and regularity of margins, were similar in the group with HT compared with the group without HT. When the histopathologic characteristics of papillary thyroid carcinoma in patients with and without HT were compared, again there was no significant difference. CONCLUSIONS We suggest that there is an association between HT and TC, and HT may predispose to the development of TC. This indicates the need for close observation of neoplastic changes in patients with HT. Nevertheless, the presence of HT seems to have no effect on the US and histopathologic characteristics of malignant nodules in TC patients. This finding may indicate that evaluation of nodules and initial treatment of TC in these patients does not require different management.

The Value of Fine-Needle Aspiration Biopsy in Subcentimeter Thyroid Nodules

BACKGROUND The need to perform fine-needle aspiration biopsy (TFNAB) on subcentimeter thyroid nodules is less clear than for larger nodules. We compared the ultrasonographic features of thyroid nodules less than and greater than one centimeter and correlated this information with the cytological results for TFNAB and the final histopathological diagnosis in selected patients. METHODS We evaluated 520 thyroid nodules (247 subcentimeter [group 1], 273 supracentimeter [group 2]) in 426 patients. Ultrasonography-guided fine-needle aspiration biopsy was performed on all nodules. Surgery was recommended for patients with TFNAB results that were read as malignant or suspicious. The results of ultrasonography, TFNAB, and histopathology were compared between the groups. RESULTS Out of 426 patients, 337 had one nodule, 84 had two, and five had three. There was indeterminate cytology in 20 cases, 10 from each group. Inadequate cytology was obtained in 41/247 (16.6%) nodules in group 1 and 61/273 (22.3%) nodules in group 2, and the difference in rate was not significant (p = 0.067). The malignancy rate as determined by TFNAB was 4.9% in group 1 and 1.5% in group 2 (p < 0.025). In patients who underwent surgery for thyroid nodules the malignancy rate was 6% in group 1 and 2.9% in group 2 (p = 0.08). Hypoechoic pattern, microcalcification, and a long axis/short axis ratio (LA/SA) of < 1.5 were associated with malignancy in subcentimeter thyroid nodules (group 1), while only a hypoechoic pattern was associated with malignancy in supracentimeter thyroid nodules (group 2). CONCLUSIONS The incidence of cancer in thyroid nodules < 1 cm does not appear to be lower than in larger nodules and may even be higher. Physicians should consider obtaining biopsy samples from subcentimeter hypoechoic nodules that contain microcalcification and have a relatively round shape (LA/SA < 1.5).

Effects of percutaneous laser ablation treatment in benign solitary thyroid nodules on nodule volume, thyroglobulin and anti-thyroglobulin levels, and cytopathology of nodule in 1 yr follow-up

Objective: To investigate the effects of ultrasound (US)-guided percutaneous laser ablation (PLA) in the treatment of benign solid hypoactive thyroid nodules on nodule volume, thyroid functions, nodule cytology and patients’ complaints. Material and method: Criteria for enrollment in the study were as follows: patients with euthyroid, benign, hypofunctional nodule who had compressive symptoms or cosmetic complaints, but considered inoperable, or who rejected surgical treatment. PLA procedure at 3–5 watts (W) was applied to 15 thyroid nodules of 12 patients (4 male and 8 female; age range 20–78 yr, mean age 47.42±17.05 yr), and patients were followed up for 12 months. Thyroid functions and nodule volumes (ultrasonographically) were evaluated. US-guided fine needle aspiration biopsy (FNAB) was performed before and after the procedure, and biopsy specimens were cytologically evaluated. Results: The mean nodule volume before the procedure was 11.97 ml (min-max 0.95–26.30 ml). However, 12 months after the procedure the mean nodule volume was 2.21±2.32 ml (min–max 0.10–7.65 ml). The mean reduction in nodule volumes was 82%. Thyroglobulin levels reached peak values at 1 month after the procedure, and anti-thyroglobulin levels at 3 months after the procedure. FNAB performed at 12th month showed neutrophil polymorphs, macrophages, abundant cell debris, colloid, multinucleated giant cells, and small fragments of fibrous stroma which indicated that PLA procedure led to degenerative changes in nodules. Conclusion: US-guided PLA is a new, successful treatment method which is reliable in the long term in benign solid thyroid nodules for selected patients who are inoperable or do not prefer surgery.

Preoperative and Postoperative Evaluation of Thyroid Disease in Patients Undergoing Surgical Treatment of Primary Hyperparathyroidism

OBJECTIVE To evaluate the occurrence of thyroid disease in patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS In this case series, records of all patients with a diagnosis of primary hyperparathyroidism who underwent parathyroidectomy between January 2005 and December 2008 in our clinic were analyzed retrospectively. Preoperatively, all patients were evaluated with ultrasonography and parathyroid scintigraphy; when needed, thyroid scintigraphy and ultrasound-guided fine-needle aspiration biopsy (FNAB) were used. All patients underwent standard neck exploration. Postoperative histopathologic findings of thyroid tissue were classified as nodular/multinodular hyperplasia, Hashimoto thyroiditis, papillary thyroid carcinoma, or normal. RESULTS Fifty-one women and 9 men were included. In the 60 patients, preoperative ultrasonography revealed thyroiditis (without nodules) in 13 (22%), a solitary nodule in 9 (15%) (coexistent with thyroiditis in 7 patients), multinodular goiter in 24 (40%) (coexistent with thyroiditis in 5 patients), and normal findings in 14 (23%). Rates of thyroiditis and nodular goiter were 42% and 55%, respectively. Collectively, prevalence of thyroid disease was 77%. Total thyroidectomy was performed in 27 patients, and hemithyroidectomy was performed in 15 patients. Indications for total thyroidectomy were nondiagnostic or suspicious FNAB results in 5 patients, hyperthyroidism in 4 patients, ultrasonography findings in 11 patients, and intraoperatively recognized suspicious nodularity in 7 patients. Postoperatively, thyroid carcinoma was diagnosed in 9 patients (15%). CONCLUSIONS Thyroid disease, particularly thyroid carcinoma, is common in patients with primary hyperparathyroidism. This association should be considered when selecting the surgical procedure. Intraoperative evaluation of the thyroid is as important as preoperative evaluation with ultrasonography and FNAB in patients with thyroid disease and primary hyperparathyroidism.

CA 19-9 level in patients with type 2 diabetes mellitus and its relation to the metabolic control and microvascular complications.

Introduction:The aim of this study is to compare CA 19-9 levels in patients with type 2 diabetes mellitus (DM) and healthy control group. The relation of CA 19-9 levels to metabolic control and microvascular complications in patients with diabetes was also investigated. Methods:Three hundred forty patients with type 2 DM and age-, sex- and body mass index-matched 214 healthy controls group were included in the study. HbA1c, duration of DM and microvascular complications of DM were reviewed. CA 19-9 levels (normal range, 0–35 U/mL) were measured in all participants. Results:Median CA 19-9 level was significantly higher in patients with diabetes compared with control group [19.5 U/mL (0–214.8 U/mL) versus 7.4 U/mL (0.4–47.0 U/mL)] (P < 0.001). Prevalence of high CA 19-9 levels in patients with diabetes was 31.2%, and CA 19-9 level was positively correlated with age, duration of diabetes, HbA1c and number of complications. Effects of duration of diabetes, HbA1c and diabetic nephropathy were still continuing in multiple linear regression analysis. Using regression coefficients of all variables in multiple regression analysis, this study tried to determine a new cutoff value for CA 19-9 level in patients with diabetes. The cutoff value at 97th percentile was 57.14 U/mL. Conclusions:High CA 19-9 value in patients with diabetes may indicate the need for a careful evaluation of blood glucose regulation and investigation of complications. Defining a new cutoff value in these patients would prevent unnecessary laboratory or imaging procedures.

Subcapsular Hematoma Complication During Percutaneous Laser Ablation to a Hypoactive Benign Solitary Thyroid Nodule

Ultrasound (US)–guided percutaneous laser ablation (PLA) is a new procedure for reducing the size of large nonfunctioning thyroid nodules (1–5). It has also been used to treat autonomously functioning thyroid nodules (6–9), and was employed for palliative purposes in two cases with anaplastic thyroid carcinoma (7,10). Although fine-needle aspiration biopsy (FNAB) may be complicated by hematoma formation, there are few, if any, reports of this occurrence after PLA treatment of thyroid nodules. We would like to report this complication. A 42-year-old man with an apparently otherwise unremarkable past medical history presented with swelling of the neck and difficulty in breathing and swallowing. Physical examination revealed a 4 cm, mobile, nontender nodule of medium consistency in the right lobe of the thyroid. Serum TSH, free T4, free T3, thyroglobulin, and calcitonin were normal, and tests for antibodies to thyroid peroxidase and thyroglobulin were negative. Ultrasonography was performed by Pro 200 Scanner (GE Medical Systems, Kyunggido, Korea), and a 16.8 mL solid nodule was observed in right lobe of the thyroid. Scintigraphy performed by Technetium-99m (99mTc) showed a cold nodule in the right lobe of the thyroid. FNAB of the nodule was read as benign. The patient refused surgery but agreed to undergo PLA. Informed consent for this procedure was given by the patient, and the hospital’s ethics committee approved it. Because of the large size of the nodule, the procedure was planned in two stages, first the inferior half of the nodule and then the superior half. A 32mm, 21-gauge (0.8 mm) needle was custom manufactured for the first procedure. Sedation was obtained with 7.5 mg diazepam (SABA Pharmaceuticals, Istanbul, Turkey) 1 hour prior to the procedure. After subcutaneous injection of 2 mL 2% lidocaine, the custom-produced needle was inserted with US guidance, into inferior part of nodule along its long axis. The proper position of needle tip within the nodule was confirmed by two-plane US images. Then, a bare flat-end fiber, 400 mm in diameter, was inserted through needle lumen. The fiber tip was aligned with the needle tip. Then, the fiber tip was advanced 5 mm to provide direct contact with the tissue. Two-plane US images were obtained to confirm that the fiber tip was at least 2 cm from surrounding vital structures like esophagus, laryngeal nerve, and trachea. Laser ablation was performed by an electronic infrared diode laser at 810 nm wavelength using a Gallium-AluminumArsenide (GaAlAs) power source (model 15 plus; Diomed, Cambridge, UK) (1,2,4,6,9,10). A total of 720 J of energy was transferred within 240 seconds with 3 W power. US after this initial procedure showed a hypoechoic region under the capsule in the inferior–anterior part of nodule. The patient, however, did not experience any unusual pain or change in breathing or swallowing. The second part of procedure was cancelled, and records of the first procedure were examined. The usual changes associated with the procedure started to appear at 70 seconds. Thirty seconds later, at 100th second, a hypoechoic area started to appear and later expanded in the inferior–anterior subcapsular region of the nodule. The patient was hospitalized and monitored closely with the surgical team. Cross-sectional diameter of the hypoechoic area was 10 mm in transverse axis, 20 mm in vertical axis, and 10 mm in longitudinal axis. Its volume was calculated to be 1.04 mL. Volume of an ellipsoid object is calculated by the formula V1⁄4 (a b c) p=6, where a, b, and c are dimensions of the object. Because the hypoechoic area was not vascular in color Doppler US, diagnosis of arterial or venous pseudoaneurysm was excluded, and the area was considered as a hematoma. Forty-eight hours after the procedure, dimensions of the hematoma had regressed to 4 mm in transverse axis, 2 mm in vertical axis, and 10 mm in longitudinal axis. By 1 month after the procedure the hematoma had completely resorbed. The history was again taken from the patient, and this time he indicated that he had taken 300 mg acetyl salicylic acid daily for 1 year. He had not given this history initially because he did not think that it was important as far as the procedure was concerned. The most common complication of PLA for thyroid nodules is pain in the neck (1–9,11–14). It is often a burning-like sensation that develops during the procedure and begins to cease immediately after the cessation of the procedure. Analgesic drugs are usually not needed for this pain. Complaint of pain during swallowing occurred in these cases for 3–7 days, and completely resorbed at 7th day by application of paracetamol 1000 mg=day (4). Neck pain developing after the procedure is usually moderate, and may be referred to the shoulder and can last for up to 8 days. In some cases acetyl THYROID Volume 18, Number 8, 2008 a Mary Ann Liebert, Inc. DOI: 10.1089=thy.2007.0338

Percutaneous laser ablation of an autonomous thyroid nodule: effects on nodule size and histopathology of the nodule 2 years after the procedure.

Ultrasound (US)–guided percutaneous laser ablation (PLA) is a new procedure for decreasing the size of thyroid nodules (1–5). It has been used to treat compressive symptoms in benign solitary cold thyroid nodules (1–5) and to reduce thyroid hormone production in autonomous functioning thyroid nodules (6–9). In two cases of anaplastic thyroid carcinoma, it was used for palliative purposes (7,10). Pacella et al. (11) first described thermal injury of thyroid tissue by PLA. We previously studied the effects of PLA on the cytology of hypofunctioning thyroid nodules, nodule volume, and thyroid function, but did not report data on histopathologic changes produced by US-guided PLA in thyroid nodules (4). We now describe the histopathology of an autonomously functioning thyroid nodule 2 years after PLA. A 25-year-old woman presented with swelling of the neck and difficulty breathing. On physical examination, a nontender, mobile, moderately firm nodule of about 3 cm was noted in the right lobe of the thyroid. Serum thyrotropin (thyroid-stimulating hormone, TSH) was 0.55 mIU=mL (normal range: 0.4–4 mIU=mL), serum free thyroxine level was 1.21 ng=dL (normal range: 0.85–1.78 ng=dL), and serum free triiodothyronine level was 3.85 pg=mL (normal range: 1.57– 4.71 pg=mL), all within normal limits. Serum antithyroid peroxidase antibody was 5 IU=mL (normal range: 0–35 IU=mL), anti-thyroglobulin antibody (anti-TgAb) was 10 IU=mL (normal range: 0–40 IU=mL), serum Tg level was 10 ng=mL (normal range: 0–55 ng=mL), and serum calcitonin level was 1 pg=mL (normal range: 5.0–11.5 pg=mL). US was performed using a Pro 200 Scanner (GE Medical Systems Kyunggido, Korea), and a 13.50 mL solid nodule was detected in the right lobe of the thyroid. Echogenity was normal in the remaining thyroid tissue. Technetium-99m (Tc) scintigraphy showed a hot nodule in the right lobe, with slight suppression of 99m Tc uptake in the remainder of the thyroid (Fig. 1). US-guided fine-needle aspiration biopsy of the nodule showed benignappearing thyrocytes, which formed occasional follicles. The patient refused surgery or radioiodine treatment. PLA of the thyroid nodule was advised, and she accepted and gave informed consent to the procedure. The approval of the local ethics committee was obtained (Ataturk Education and Research Hospital, Ankara; date: 09.11.2004; record no.: 2004=10=009). A 16-mm-long, 21-gauge (0.8 mm) needle was custommanufactured for the nodule. Sedation was obtained with 7.5 mg diazepam (SABA Pharmaceuticals, Istanbul, Turkey) 1 hour prior to the procedure. The skin above the nodule was sterilized with 95% ethanol, and 2 mL of 2% Lidocaine was injected subcutaneously. The custom-produced needle was inserted under US guidance into the proper position within the nodule along its long axis. Then, a bare flat-end fiber, 400mm in diameter, was inserted through needle lumen. The fiber tip was aligned with the needle tip, and then advanced 5 mm to provide direct contact with thyroid tissue. Two-plane US imaging was used to confirm that the fiber tip was at least 2 cm from surrounding vital organs. A total of 3000 J of energy was transferred through the fiber tip within 600 seconds with 5 W power by an electronic infrared diode laser at 810 nm wavelength using a gallium-aluminumarsenide power source (model 15 plus; Diomed, Cambridge, UK) (1,2,4,6,9,10). The patient experienced neck discomfort and pain extending toward the chin. The pain ceased after power transfer was stopped, and no complications were encountered after the procedure. Indirect laryngoscopic examinations before and after the procedure were normal. The thyroid nodule volume, which was 13.50 mL before the procedure, decreased to 8.40 mL 3 months later and to 4.20 mL 6 months after PLA. The patient’s compression symptoms (difficulty in breathing and difficulty in swallowing) decreased from 7 points to 2 points when evaluated by visual analog scale (min, 0; max, 10) (1,2,4). Nine months after PLA, however, the volume of the nodule had increased to 5.5 mL; at 1 year it was 6.6 mL; at 2 years it was 10 mL. Serum TSH, triiodothyronine, and thyroxine remained normal, but serum anti-TgAb level, which was 10 IU=mL before the procedure, increased to 150 IU=mL at the 6th month and regressed to 60 IU=mL at the 24th month. US-guided fine-needle aspiration biopsy was performed 1 year after PLA and showed no evidence of malignancy. Scintigraphies performed at 12th and 24th months by Tc showed that the hot nodule was still present, but serum TSH was normal (0.72mIU=mL) at 24 months. The patient felt that the size of the nodule was increasing, and the visual analog scale was increased to 7 points. Therefore, thyroidectomy was advised, and the patient agreed to this. The patient underwent complete resection of the right lobe, which contained the nodule, isthmusectomy, and near-total resection of the left lobe. Macroscopic examination showed a white-gray lesion in the region of the nodule, surrounded by hemorrhagic areas (Fig. 2). Rare old and new hemorrhagic regions, minimal fibrosis, and multiple microfollicles with colloid in their lumen were observed (Fig. 3) on histopathological examination. In the thyroid tissue surrounding the nodule, lymphoid cells with occasional germinal centers were observed (Fig. 4). Also, lymphocytic infiltration was observed in the opposite lobe. PLA-induced thermal injury in human thyroid tissue was first described by Pacella et al. (11). They reported the histopathology of single nodules in two patients whose THYROID Volume 18, Number 7, 2008 a Mary Ann Liebert, Inc. DOI: 10.1089=thy.2007.0316

Assessment of left ventricular functions by tissue Doppler echocardiography in patients with Cushing's disease

Objective: To verify whether tissue Doppler imaging (TDI) could contribute to a better understanding of the natural history of cardiomyopathy in active Cushing’s disease (CD), through its enhanced sensitivity to diastolic dysfunction, and identifying preliminary regional signs of systolic dysfunction before the appearance of clinical symptoms of cardiac pathologies. Methods: Eleven women with newly diagnosed CD and 32 control cases, purposely matched for gender, age, body mass index and co-incidental diseases were enrolled in this study. Echocardiographic examinations were assessed by conventional echocardiography and tissue Doppler imaging. The peak systolic velocity (S’m), early diastolic myocardial peak velocity (E’m), late diastolic myocardial peak velocity (A’m), isovolumic acceleration (IVA), myocardial pre-contraction time (PCT’m), myocardial contraction time (CT’m) and myocardial relaxation time (RT’m) were measured at septal and lateral mitral anulus. Results: In TDI, E’m and, E’m/A’m ratio were significantly lower, and PCT’m/CT’m ratio was higher, S’m, A’m, peak early diastole/E’m ratio, PCT’m, and isovolumetric myocardial relaxation time values were similar at lateral and septal anulus in patients with CD than controls (p>0.05). Lateral and septal anulus IVA were significantly lower in patients with CD than the control group (p<0.05). Correlation analysis showed that IVA time at lateral anulus correlated positively with S’m at lateral anulus (r=0.58; p=0.002) and IVA time at septal anulus correlated positively with S’m at septal anulus (r=0.51; p=0.008). Conclusion: Our study confirms that patients with CD have impaired diastolic function. More importantly, we also demonstrated an impairment of myocardial systolic function in patients with CD by TDI. We recommend using TDI in addition to conventional echocardiography parameters for the cardiovascular risk assessment of patients with Cushing’ syndrome.

Early severe pre-eclamptic findings in a patient with Cushing's syndrome.

Cushings syndrome occurs rarely in pregnancy because of ovulatory disturbances including anovulation which is caused by hypercortisolism, but it can cause maternal complications such as hypertension, gestational diabetes, spontaneous abortion, premature birth, pre-eclampsia and stillbirth. Herein we present the case of a 22-year-old patient in the 11th week of pregnancy who was admitted to our hospital with Cushings syndrome complicated by early pre-eclampsia. Severe pre-eclampsia has high maternal and perinatal morbidities, and therefore the possibility of this complication requires that Cushings syndrome, although rare in pregnancy, be given a high clinical suspicion. Medical therapy and/or surgical therapy should be considered promptly to influence outcome favorably.

Frequency of isolated maternal hypothyroxinemia in women with gestational diabetes mellitus in a moderately iodine-deficient area

Abstract Aim: To investigate frequency of isolated maternal hypothyroxinemia (IMH) in women with gestational diabetes mellitus (GDM) using both the method specific trimester range (MSTR) and the standard reference range (SRR). Methods: Our study included 50 GDM patients (case group) and 60 non-GDM pregnant (control group). Glucose, insulin, HOMA-IR, fT4 and TSH values were measured when pregnancy was confirmed in all participants. Thyroid function tests were measured in each trimester using the SRR and the MSTR. Results: In the second and third trimesters, mean fT4 levels were significantly lower in the case group compared to the control group, based on the SRR (p < 0.001). Mean fT4 levels were within the normal reference range in both groups, based on the MSTR; however, the levels were significantly lower in the case group (p < 0.001). Using the SRR, IMH frequencies in the second and third trimesters, in the case group were 56 and 86%, respectively, and were 13.3 and 46.7%, respectively, in the control group (p < 0.001). Using the MSTR, the IMH frequencies in the second and third trimesters were 8 and 14%, respectively; there were no instances of IMH in the control group. Conclusion: This study shows that changes in glucose metabolism may affect the thyroid hormone levels (fT4). Additionally, evaluating thyroid function tests in GDM patients using the MSTR can give more accurate results.