Sonographic Appearance of Thyroid Glands in Patients Treated with Intensity-Modulated Radiotherapy or Conventional Radiotherapy for Nasopharyngeal Carcinoma Sammy C.H. Cheng, MPhil,1 Vincent W.C. Wu, PhD,1 Dora L.W. Kwong, MD,2 C.Y. Lui, MD,3 Ashley C.K. Cheng, MD,3 Brian C.W. Kot, PhD,1 Michael T.C. Ying, PhD1 1
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong SAR, China 2 Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 3 Department of Oncology, Princess Margaret Hospital, Laichikok, Kowloon, Hong Kong SAR, China Received 22 June 2014; accepted 12 July 2014
ABSTRACT: Background. This study aimed to investigate the sonographic appearances of the thyroid glands in nasopharyngeal carcinoma (NPC) patients whose cervical lymph nodes were treated with conventional radiotherapy (RT) or intensity-modulated radiotherapy (IMRT). The post-RT sonographic appearances of the thyroid glands in NPC patients were also correlated with the thyroid function. Methods. One hundred and three NPC patients who had completed RT of cervical lymph nodes using the anterior cervical field, 30 NPC patients who had completed RT of cervical lymph nodes using IMRT, and 61 healthy subjects were included in the study. Thyroid glands were sonographically assessed for their size, echogenicity, vascularity, and internal architecture. Thyroid function tests were also performed on each subject. Results. In comparison with the patients with abnormal thyroid function, the thyroid glands of the patients with normal thyroid function tended to be homogeneous and to have greater volume and echogenicity index (p < 0.05). Compared with those of the healthy subjects, the thyroid glands of patients previously treated with IMRT and those treated with the anterior cervical field showed significantly lower thyroid volume, lower incidence and number of nodules, and higher vascularity index (p < 0.05). Conclusions. The patient’s history of previous RT should be taken into consideration in the sonographic Correspondence to: M. Ying C 2014 Wiley Periodicals, Inc. V
210
C 2014 examination of the thyroid gland post-RT. V Wiley Periodicals, Inc. J Clin Ultrasound 43:210–223, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22222
Keywords: thyroid; hypothyroidism; nasopharyngeal carcinoma; ultrasonography; radiotherapy
E
xternal beam radiotherapy (RT) is commonly used to treat nasopharyngeal carcinoma (NPC) in Hong Kong. Because there is a high incidence (60–96%) of associated cervical lymph node metastases,1 an anterior cervical field is also used to irradiate cervical lymph nodes in all patients. Because the anterior cervical field to the neck involves irradiation of the thyroid gland, post-RT thyroid disorders are common in these patients.2 Hypothyroidism is the most common post-RT manifestation in patients with head and neck cancer, occurring in 20–30% of the patients.2–4 Hypothyroidism may manifest with a number of symptoms, including skin dryness, depression, chronic fatigue, weight gain, constipation, and cold intolerance, which seriously impair patients’ health and quality of life.5–7 Persistent high thyroid-stimulating hormone (TSH) level in patients could increase the risk of thyroid cancer by 15–53 times compared with the nonirradiated population.7–12 Hence, early detection of RT-induced hypothyroidism or other thyroid JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
disorders is necessary for early disease management to sustain a patient’s health status and prevent thyroid cancer development. Thyroid-function tests (TSH and free thyroxine [fT4]) are commonly used to assess thyroid dysfunction,13 especially hypothyroidism, in patients with head and neck cancer after RT. Although these tests assess thyroid function, they cannot assess the morphologic changes and vascular damage in post-RT thyroid glands that can be evaluated by sonography (US). US has been widely used for assessing the thyroid glands. Post-RT changes apparent on US scanning must be identified so that these changes are not misinterpreted. Intensity-modulated radiotherapy (IMRT) has the advantage of effective sparing of organs at risk and, at the same time, providing accurate dose conformity to the tumor, which might reduce possible radiation-induced damage to the thyroid glands during cervical lymph node RT. Therefore, this study aimed to determine the value of US in identifying post-RT changes of thyroid glands in NPC patients treated with conventional RT and those treated with IMRT.
PATIENTS AND METHODS
Study Subjects The first part of this study involved the comparison between patients with normal and those with abnormal thyroid function. A total of 103 NPC patients (70 men and 33 women) who had finished RT with the cervical lymph nodes having been treated with an anterior cervical field between 2000 and 2008 in Queen Mary Hospital (QMH) were recruited in the study. The age of the patients ranged from 24 to 71 years old (mean age 6 SD, 50.2 6 9.1 years). Another 30 NPC patients (20 men and 10 women) who had completed RT with the cervical lymph nodes treated with IMRT between 2006 and 2008 in Princess Margaret Hospital (PMH) were also recruited. The age range of these 30 patients was 29 to 81 years old (mean 6 SD, 53.0 6 13.0 years). On the basis of the results of the thyroid function tests, the patients were categorized into normal thyroid function (normal TSH and fT4 levels) and abnormal thyroid function (abnormal TSH and/ or fT4 level) groups. The sonographic appearance of the thyroid glands in patients those two groups were then compared. Patients with recurrent disease or block dissection of the neck were excluded. Patients who VOL. 43, NO. 4, MAY 2015
had undergone previous thyroidectomy or had known thyroid diseases were also excluded. All patients were recruited when they attended follow-up visits in the hospitals, and the clinical history of patients was reviewed by oncologists before recruitment. In the second part of the study, the thyroid glands of the healthy subjects and the patients treated with different RT techniques were compared. Of the 103 NPC patients recruited from QMH, 39 (30 men and 9 women) who had finished RT between 2005 and 2007 were involved. The age range of these 39 patients was 32 to 62 years old (mean 6 SD, 47.8 6 7.8 years). The 30 NPC patients recruited from PMH and described above were also involved in this part of the study. In addition, a total of 61 healthy subjects (32 men and 29 women) were recruited as the control group. Subjects with a clinical history of any cancer or thyroid disease were excluded. The age range of the healthy subjects was 27 to 82 years old (mean 6 SD, 47.0 6 9.8 years). This study was approved by the Human Subjects Ethics Subcommittee of our university. Written informed consent was obtained from all patients and healthy subjects. Each participant underwent a thyroid examination by US and blood testing for evaluation of their thyroid function. Those evaluations were arranged so that they were performed 2 to 3 years after their completion of RT. Thyroid Examination by US A thyroid examination by US was performed on all NPC patients and healthy subjects. All those examinations were performed by using an HD11 XE or HD11 US unit equipped with a 5– 12-MHz linear-array transducer (Philips Medical Systems, Bothell, WA). The right and left thyroid lobes were scanned separately on both transverse and longitudinal planes. Patients and/or subjects with incidental detection of thyroid nodule(s) on US were identified and the lesions documented. To measure volume, the craniocaudal (CC), lateromedial (LM), and anteroposterior (AP) dimensions of the thyroid lobe were measured. The LM and AP dimensions were measured on the transverse scan showing the maximum crosssectional area of the thyroid lobe. The CC dimension was measured on the longitudinal scan of the thyroid lobe. The thyroid volume was determined as the sum of the volumes of the left and right thyroid lobes, and the thyroid 211
CHENG ET AL
FIGURE 1. Transverse gray-scale sonogram shows measurement of the echo-intensity of a normal thyroid gland (red line) and the adjacent sternocleidomastoid muscle (yellow line) by outlining their boundaries using the software QLab. The echo-intensity of the thyroid gland (region of interest [ROI] 1) and the sternocleidomastoid muscle (ROI 2) are shown in the right upper corner of the image.
lobe volume was calculated by the following previously described equation14: Thyroid lobe volume 5 0:38 ðCC LM APÞ 1 1:76 The echogenicity of the thyroid gland was assessed and subjectively classified as hypoechoic, isoechoic, or hyperechoic relative to that of the adjacent sternocleidomastoid muscle. Multiple transverse sonograms of the thyroid gland were obtained. Archived images were retrieved after the US examination, and the echogenicity of the thyroid gland and sternoclei-
Echogenicity index 5
Mean echogenicity of the thyroid lobe Mean echogenicity of the sternocleidomastoid muscle
The mean echogenicity index of the entire thyroid gland was the mean value of the echogenicity indices of the left and right thyroid lobes. Hypoechoic thyroid glands tended to have a lower echogenicity index, whereas hyperechoic glands tended to have a higher echogenicity index. The echotexture of the thyroid glands was also assessed: it was considered homogeneous when its parenchyma showed uniform echogenicity and heterogeneous when it demonstrated nonuniform parenchyma. To assess the thyroid gland’s vascularity, power Doppler US was used. Multiple sonograms were taken at different parts of the thyroid glands. In each thyroid lobe, the three 212
domastoid muscle were quantified by using QLab software (Philips Medical Systems). To quantify the echogenicity of those structures, their boundaries were outlined manually, and the echogenicity values were determined automatically by the built-in software (Figure 1). On each side of the neck, three images with a relatively homogeneous echotexture and larger cross-sectional area of the thyroid lobe were selected and measured. The mean value of the echogenicity of the thyroid lobe and that of the sternocleidomastoid muscle were measured. The echogenicity index of the thyroid lobe was then defined as follows:
images with the most abundant thyroid vascularity were used, and for each sonogram, the degree of thyroid vascularity was assessed by using a customized algorithm with MATLAB software.15 In evaluating the degree of thyroid vascularity, the boundaries of the thyroid lobe (ie, the region of interest, ROI) were outlined manually on the sonogram. The customized algorithm extracted the ROI from the US image and measured the total number of pixels in it. Subsequently, the color pixels (ie, pixels other than gray-scale) were extracted from the ROI and their number was calculated (Figure 2). The vascularity index (degree of vascularity) of each thyroid lobe was then defined as follows: JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
FIGURE 2. Sonograms demonstrate the extraction of color pixels in the region of interest (ROI) for measurement of the vascularity index of the thyroid gland.
Vascularity index 5
Number of color pixels within the ROI Total number of pixels within the ROI
The mean thyroid vascularity index of the whole thyroid gland was the mean value of the vascularity indices of the left and right thyroid lobes. Thyroid Function Tests Each NPC patient and healthy subject had 5 mL of blood drawn by venipuncture into a heparinized tube. Plasma was extracted after centrifugation at 2,500 rpm for 10 minutes at 4 C and was then stored frozen at 225 C until being tested. Before the test, the plasma was thawed at room temperature for 30 minutes. An automated VIDAS analyzer (BioMerieux, Marcy l’Etoile, France) was used to measure the thyVOL. 43, NO. 4, MAY 2015
roid hormone levels. The plasma TSH level was measured by using analytical reagent kits for TSH (VIDAS; BioMerieux China Ltd., Jiangmen, Guangdong, China), and the plasma fT4 level was evaluated with analytical reagent kits for fT4 (VIDAS). A TSH level between 0.27 and 4.7 mIU/mL and an fT4 level between 9 and 20 pmol/L were considered to be normal.16,17 TSH and fT4 levels out of those ranges were considered abnormal. Evaluation of Thyroid Gland RT Dose For NPC patients with cervical lymph nodes that had been treated with an anterior cervical field at QMH, the total mean thyroid dose was 213
CHENG ET AL
evaluated by using isodose display, the dose–volume histogram, and associated dosimetric parameters provided by the treatment planning system. For NPC patients with cervical lymph nodes that had been treated with IMRT at PMH, the RT treatment plan was retrieved from the treatment planning system. The treatment plans were computed according to the planning criteria of the corresponding techniques. Statistical Analysis In the data analysis, the study findings were compared between the patients and healthy subjects with normal thyroid function and those with abnormal thyroid function as well as between the healthy subjects and the patients treated with different RT techniques. For the comparison between patients with normal and those with abnormal thyroid function, the statistical significance of the differences in thyroid volume, echogenicity index, vascularity index, number of nodules, and level of TSH and fT4 were calculated by using MannWhitney testing. Fisher’s exact testing was used to calculate the level of significance of the differences in thyroid echogenicity and echotexture and the incidence of thyroid nodules between the two groups. The levels of significance of the differences in thyroid volume, thyroid echogenicity index, thyroid vascularity index, number of nodules, and the levels of TSH and fT4 between the healthy subjects, the patients with cervical nodes treated with an anterior cervical field, and the patients with cervical nodes treated with IMRT were calculated with the Kruskal-Wallis test. When a significant difference (p < 0.05) was identified, Dunn’s Multiple Comparison test was used post hoc. Fisher’s exact testing was used to calculate the levels of significance of the differences between the three study groups in thyroid echogenicity and echotexture and the incidence of thyroid nodules. p values < 0.05 were considered to be statistically significant. GraphPad InStat software was used for the statistical analyses (GraphPad Software Inc., San Diego, CA). In addition to that testing, the optimal cutoff values of thyroid volume and echogenicity index for distinguishing between normal and abnormal thyroid function were evaluated. A total of 36 cutoff values with an interval of 0.5 cm3 for thyroid volume (from 5.0–22.5 cm3) and 25 cutoff values with an interval of 0.2 for echogenicity index (from 0.8–5.6) were evaluated for their 214
sensitivity and specificity in the differential diagnosis. A thyroid gland with abnormal thyroid function (ie, either TSH or fT4 level out of the normal ranges) that showed a thyroid volume smaller than the selected cutoff value was considered to be a true-positive finding, whereas the thyroid gland with abnormal function but a volume equal to or greater than the selected cutoff value was considered to be a falsenegative finding. Likewise, a thyroid gland with normal thyroid function (ie, TSH and fT4 levels within the normal ranges) that showed a thyroid volume equal to or greater than the selected cutoff value was considered to be a true negative, and a thyroid volume smaller than the selected cutoff value was considered to be a false positive. The sensitivity and specificity were calculated and used to plot the receiver operating characteristic (ROC) curve. In the assessment of the thyroid echogenicity index, a thyroid gland with abnormal thyroid function and an echogenicity index smaller than the selected cutoff value was considered a true positive, whereas an echogenicity index equal to or greater than the selected cutoff value was considered to be a false negative. Likewise, a thyroid gland with normal function and an echogenicity index equal to or greater than the selected cutoff value was considered a true negative, whereas an echogenicity index smaller than the selected cutoff value was considered a false positive. The sensitivity and specificity were calculated and used to plot the ROC curve.
RESULTS
Part I: Comparison Between Patients with Normal Thyroid Function and Those with Abnormal Thyroid Function In total, 133 thyroid glands (266 thyroid lobes) from the 133 NPC patients from QMH and PMH were evaluated with US and thyroid function testing. Thyroid function tests demonstrated that 38 patients had abnormal thyroid function; they were categorized into the abnormal thyroid function group. The other 95 patients showed normal thyroid function and were included in the normal thyroid function group. Results indicated that the mean TSH level of the abnormal thyroid function group (9.32 mIU/ mL) was significantly greater than that of the normal thyroid function group (2.55 mIU/mL; JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
p < 0.0001, Table 1), whereas the mean fT4 level within the abnormal thyroid function group (8.67 pmol/L) was significantly lower than that of the normal thyroid function group (11.35 pmol/L; p < 0.0001, Table 1). For the 38 patients with abnormal thyroid function, the mean thyroid dose was 62.6 6 4.9 Gy, and that for the 95 patients with normal thyroid function was 62.6 6 5.6 Gy. There was no significant difference in the mean thyroid dose between the two groups (p 5 0.79). Results showed that the mean thyroid volume of normal thyroid function group (9.57 cm3) was significantly greater than that of the abnormal thyroid function group (8.06 cm3; p < 0.0001, Table 1). In addition, the mean thyroid echogeTABLE 1 Mean Characteristics of the Thyroid Glands on Sonography in Postradiotherapy Patients with Nasopharyngeal Carcinoma with Normal Thyroid Function versus Those with Abnormal Thyroid Function Mean 6 SD
Sonographic Appearance Thyroid volume (cm3) Echogenicity index Vascularity index Number of nodules TSH level (mIU/mL) fT4 level (pmol/L)
Normal Thyroid Function Group
Abnormal Thyroid Function Group
p Value*
9.57 6 2.60 2.32 6 0.88 29.64 6 11.31 0.45 6 0.82 2.55 6 0.99 11.35 6 1.53
8.06 6 2.39 2.03 6 0.99 29.28 6 12.14 0.58 6 0.86 9.32 6 9.87 8.67 6 1.50
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong SAR, China 2 Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 3 Department of Oncology, Princess Margaret Hospital, Laichikok, Kowloon, Hong Kong SAR, China Received 22 June 2014; accepted 12 July 2014
ABSTRACT: Background. This study aimed to investigate the sonographic appearances of the thyroid glands in nasopharyngeal carcinoma (NPC) patients whose cervical lymph nodes were treated with conventional radiotherapy (RT) or intensity-modulated radiotherapy (IMRT). The post-RT sonographic appearances of the thyroid glands in NPC patients were also correlated with the thyroid function. Methods. One hundred and three NPC patients who had completed RT of cervical lymph nodes using the anterior cervical field, 30 NPC patients who had completed RT of cervical lymph nodes using IMRT, and 61 healthy subjects were included in the study. Thyroid glands were sonographically assessed for their size, echogenicity, vascularity, and internal architecture. Thyroid function tests were also performed on each subject. Results. In comparison with the patients with abnormal thyroid function, the thyroid glands of the patients with normal thyroid function tended to be homogeneous and to have greater volume and echogenicity index (p < 0.05). Compared with those of the healthy subjects, the thyroid glands of patients previously treated with IMRT and those treated with the anterior cervical field showed significantly lower thyroid volume, lower incidence and number of nodules, and higher vascularity index (p < 0.05). Conclusions. The patient’s history of previous RT should be taken into consideration in the sonographic Correspondence to: M. Ying C 2014 Wiley Periodicals, Inc. V
210
C 2014 examination of the thyroid gland post-RT. V Wiley Periodicals, Inc. J Clin Ultrasound 43:210–223, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22222
Keywords: thyroid; hypothyroidism; nasopharyngeal carcinoma; ultrasonography; radiotherapy
E
xternal beam radiotherapy (RT) is commonly used to treat nasopharyngeal carcinoma (NPC) in Hong Kong. Because there is a high incidence (60–96%) of associated cervical lymph node metastases,1 an anterior cervical field is also used to irradiate cervical lymph nodes in all patients. Because the anterior cervical field to the neck involves irradiation of the thyroid gland, post-RT thyroid disorders are common in these patients.2 Hypothyroidism is the most common post-RT manifestation in patients with head and neck cancer, occurring in 20–30% of the patients.2–4 Hypothyroidism may manifest with a number of symptoms, including skin dryness, depression, chronic fatigue, weight gain, constipation, and cold intolerance, which seriously impair patients’ health and quality of life.5–7 Persistent high thyroid-stimulating hormone (TSH) level in patients could increase the risk of thyroid cancer by 15–53 times compared with the nonirradiated population.7–12 Hence, early detection of RT-induced hypothyroidism or other thyroid JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
disorders is necessary for early disease management to sustain a patient’s health status and prevent thyroid cancer development. Thyroid-function tests (TSH and free thyroxine [fT4]) are commonly used to assess thyroid dysfunction,13 especially hypothyroidism, in patients with head and neck cancer after RT. Although these tests assess thyroid function, they cannot assess the morphologic changes and vascular damage in post-RT thyroid glands that can be evaluated by sonography (US). US has been widely used for assessing the thyroid glands. Post-RT changes apparent on US scanning must be identified so that these changes are not misinterpreted. Intensity-modulated radiotherapy (IMRT) has the advantage of effective sparing of organs at risk and, at the same time, providing accurate dose conformity to the tumor, which might reduce possible radiation-induced damage to the thyroid glands during cervical lymph node RT. Therefore, this study aimed to determine the value of US in identifying post-RT changes of thyroid glands in NPC patients treated with conventional RT and those treated with IMRT.
PATIENTS AND METHODS
Study Subjects The first part of this study involved the comparison between patients with normal and those with abnormal thyroid function. A total of 103 NPC patients (70 men and 33 women) who had finished RT with the cervical lymph nodes having been treated with an anterior cervical field between 2000 and 2008 in Queen Mary Hospital (QMH) were recruited in the study. The age of the patients ranged from 24 to 71 years old (mean age 6 SD, 50.2 6 9.1 years). Another 30 NPC patients (20 men and 10 women) who had completed RT with the cervical lymph nodes treated with IMRT between 2006 and 2008 in Princess Margaret Hospital (PMH) were also recruited. The age range of these 30 patients was 29 to 81 years old (mean 6 SD, 53.0 6 13.0 years). On the basis of the results of the thyroid function tests, the patients were categorized into normal thyroid function (normal TSH and fT4 levels) and abnormal thyroid function (abnormal TSH and/ or fT4 level) groups. The sonographic appearance of the thyroid glands in patients those two groups were then compared. Patients with recurrent disease or block dissection of the neck were excluded. Patients who VOL. 43, NO. 4, MAY 2015
had undergone previous thyroidectomy or had known thyroid diseases were also excluded. All patients were recruited when they attended follow-up visits in the hospitals, and the clinical history of patients was reviewed by oncologists before recruitment. In the second part of the study, the thyroid glands of the healthy subjects and the patients treated with different RT techniques were compared. Of the 103 NPC patients recruited from QMH, 39 (30 men and 9 women) who had finished RT between 2005 and 2007 were involved. The age range of these 39 patients was 32 to 62 years old (mean 6 SD, 47.8 6 7.8 years). The 30 NPC patients recruited from PMH and described above were also involved in this part of the study. In addition, a total of 61 healthy subjects (32 men and 29 women) were recruited as the control group. Subjects with a clinical history of any cancer or thyroid disease were excluded. The age range of the healthy subjects was 27 to 82 years old (mean 6 SD, 47.0 6 9.8 years). This study was approved by the Human Subjects Ethics Subcommittee of our university. Written informed consent was obtained from all patients and healthy subjects. Each participant underwent a thyroid examination by US and blood testing for evaluation of their thyroid function. Those evaluations were arranged so that they were performed 2 to 3 years after their completion of RT. Thyroid Examination by US A thyroid examination by US was performed on all NPC patients and healthy subjects. All those examinations were performed by using an HD11 XE or HD11 US unit equipped with a 5– 12-MHz linear-array transducer (Philips Medical Systems, Bothell, WA). The right and left thyroid lobes were scanned separately on both transverse and longitudinal planes. Patients and/or subjects with incidental detection of thyroid nodule(s) on US were identified and the lesions documented. To measure volume, the craniocaudal (CC), lateromedial (LM), and anteroposterior (AP) dimensions of the thyroid lobe were measured. The LM and AP dimensions were measured on the transverse scan showing the maximum crosssectional area of the thyroid lobe. The CC dimension was measured on the longitudinal scan of the thyroid lobe. The thyroid volume was determined as the sum of the volumes of the left and right thyroid lobes, and the thyroid 211
CHENG ET AL
FIGURE 1. Transverse gray-scale sonogram shows measurement of the echo-intensity of a normal thyroid gland (red line) and the adjacent sternocleidomastoid muscle (yellow line) by outlining their boundaries using the software QLab. The echo-intensity of the thyroid gland (region of interest [ROI] 1) and the sternocleidomastoid muscle (ROI 2) are shown in the right upper corner of the image.
lobe volume was calculated by the following previously described equation14: Thyroid lobe volume 5 0:38 ðCC LM APÞ 1 1:76 The echogenicity of the thyroid gland was assessed and subjectively classified as hypoechoic, isoechoic, or hyperechoic relative to that of the adjacent sternocleidomastoid muscle. Multiple transverse sonograms of the thyroid gland were obtained. Archived images were retrieved after the US examination, and the echogenicity of the thyroid gland and sternoclei-
Echogenicity index 5
Mean echogenicity of the thyroid lobe Mean echogenicity of the sternocleidomastoid muscle
The mean echogenicity index of the entire thyroid gland was the mean value of the echogenicity indices of the left and right thyroid lobes. Hypoechoic thyroid glands tended to have a lower echogenicity index, whereas hyperechoic glands tended to have a higher echogenicity index. The echotexture of the thyroid glands was also assessed: it was considered homogeneous when its parenchyma showed uniform echogenicity and heterogeneous when it demonstrated nonuniform parenchyma. To assess the thyroid gland’s vascularity, power Doppler US was used. Multiple sonograms were taken at different parts of the thyroid glands. In each thyroid lobe, the three 212
domastoid muscle were quantified by using QLab software (Philips Medical Systems). To quantify the echogenicity of those structures, their boundaries were outlined manually, and the echogenicity values were determined automatically by the built-in software (Figure 1). On each side of the neck, three images with a relatively homogeneous echotexture and larger cross-sectional area of the thyroid lobe were selected and measured. The mean value of the echogenicity of the thyroid lobe and that of the sternocleidomastoid muscle were measured. The echogenicity index of the thyroid lobe was then defined as follows:
images with the most abundant thyroid vascularity were used, and for each sonogram, the degree of thyroid vascularity was assessed by using a customized algorithm with MATLAB software.15 In evaluating the degree of thyroid vascularity, the boundaries of the thyroid lobe (ie, the region of interest, ROI) were outlined manually on the sonogram. The customized algorithm extracted the ROI from the US image and measured the total number of pixels in it. Subsequently, the color pixels (ie, pixels other than gray-scale) were extracted from the ROI and their number was calculated (Figure 2). The vascularity index (degree of vascularity) of each thyroid lobe was then defined as follows: JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
FIGURE 2. Sonograms demonstrate the extraction of color pixels in the region of interest (ROI) for measurement of the vascularity index of the thyroid gland.
Vascularity index 5
Number of color pixels within the ROI Total number of pixels within the ROI
The mean thyroid vascularity index of the whole thyroid gland was the mean value of the vascularity indices of the left and right thyroid lobes. Thyroid Function Tests Each NPC patient and healthy subject had 5 mL of blood drawn by venipuncture into a heparinized tube. Plasma was extracted after centrifugation at 2,500 rpm for 10 minutes at 4 C and was then stored frozen at 225 C until being tested. Before the test, the plasma was thawed at room temperature for 30 minutes. An automated VIDAS analyzer (BioMerieux, Marcy l’Etoile, France) was used to measure the thyVOL. 43, NO. 4, MAY 2015
roid hormone levels. The plasma TSH level was measured by using analytical reagent kits for TSH (VIDAS; BioMerieux China Ltd., Jiangmen, Guangdong, China), and the plasma fT4 level was evaluated with analytical reagent kits for fT4 (VIDAS). A TSH level between 0.27 and 4.7 mIU/mL and an fT4 level between 9 and 20 pmol/L were considered to be normal.16,17 TSH and fT4 levels out of those ranges were considered abnormal. Evaluation of Thyroid Gland RT Dose For NPC patients with cervical lymph nodes that had been treated with an anterior cervical field at QMH, the total mean thyroid dose was 213
CHENG ET AL
evaluated by using isodose display, the dose–volume histogram, and associated dosimetric parameters provided by the treatment planning system. For NPC patients with cervical lymph nodes that had been treated with IMRT at PMH, the RT treatment plan was retrieved from the treatment planning system. The treatment plans were computed according to the planning criteria of the corresponding techniques. Statistical Analysis In the data analysis, the study findings were compared between the patients and healthy subjects with normal thyroid function and those with abnormal thyroid function as well as between the healthy subjects and the patients treated with different RT techniques. For the comparison between patients with normal and those with abnormal thyroid function, the statistical significance of the differences in thyroid volume, echogenicity index, vascularity index, number of nodules, and level of TSH and fT4 were calculated by using MannWhitney testing. Fisher’s exact testing was used to calculate the level of significance of the differences in thyroid echogenicity and echotexture and the incidence of thyroid nodules between the two groups. The levels of significance of the differences in thyroid volume, thyroid echogenicity index, thyroid vascularity index, number of nodules, and the levels of TSH and fT4 between the healthy subjects, the patients with cervical nodes treated with an anterior cervical field, and the patients with cervical nodes treated with IMRT were calculated with the Kruskal-Wallis test. When a significant difference (p < 0.05) was identified, Dunn’s Multiple Comparison test was used post hoc. Fisher’s exact testing was used to calculate the levels of significance of the differences between the three study groups in thyroid echogenicity and echotexture and the incidence of thyroid nodules. p values < 0.05 were considered to be statistically significant. GraphPad InStat software was used for the statistical analyses (GraphPad Software Inc., San Diego, CA). In addition to that testing, the optimal cutoff values of thyroid volume and echogenicity index for distinguishing between normal and abnormal thyroid function were evaluated. A total of 36 cutoff values with an interval of 0.5 cm3 for thyroid volume (from 5.0–22.5 cm3) and 25 cutoff values with an interval of 0.2 for echogenicity index (from 0.8–5.6) were evaluated for their 214
sensitivity and specificity in the differential diagnosis. A thyroid gland with abnormal thyroid function (ie, either TSH or fT4 level out of the normal ranges) that showed a thyroid volume smaller than the selected cutoff value was considered to be a true-positive finding, whereas the thyroid gland with abnormal function but a volume equal to or greater than the selected cutoff value was considered to be a falsenegative finding. Likewise, a thyroid gland with normal thyroid function (ie, TSH and fT4 levels within the normal ranges) that showed a thyroid volume equal to or greater than the selected cutoff value was considered to be a true negative, and a thyroid volume smaller than the selected cutoff value was considered to be a false positive. The sensitivity and specificity were calculated and used to plot the receiver operating characteristic (ROC) curve. In the assessment of the thyroid echogenicity index, a thyroid gland with abnormal thyroid function and an echogenicity index smaller than the selected cutoff value was considered a true positive, whereas an echogenicity index equal to or greater than the selected cutoff value was considered to be a false negative. Likewise, a thyroid gland with normal function and an echogenicity index equal to or greater than the selected cutoff value was considered a true negative, whereas an echogenicity index smaller than the selected cutoff value was considered a false positive. The sensitivity and specificity were calculated and used to plot the ROC curve.
RESULTS
Part I: Comparison Between Patients with Normal Thyroid Function and Those with Abnormal Thyroid Function In total, 133 thyroid glands (266 thyroid lobes) from the 133 NPC patients from QMH and PMH were evaluated with US and thyroid function testing. Thyroid function tests demonstrated that 38 patients had abnormal thyroid function; they were categorized into the abnormal thyroid function group. The other 95 patients showed normal thyroid function and were included in the normal thyroid function group. Results indicated that the mean TSH level of the abnormal thyroid function group (9.32 mIU/ mL) was significantly greater than that of the normal thyroid function group (2.55 mIU/mL; JOURNAL OF CLINICAL ULTRASOUND
ULTRASOUND OF POST-RT THYROID GLAND
p < 0.0001, Table 1), whereas the mean fT4 level within the abnormal thyroid function group (8.67 pmol/L) was significantly lower than that of the normal thyroid function group (11.35 pmol/L; p < 0.0001, Table 1). For the 38 patients with abnormal thyroid function, the mean thyroid dose was 62.6 6 4.9 Gy, and that for the 95 patients with normal thyroid function was 62.6 6 5.6 Gy. There was no significant difference in the mean thyroid dose between the two groups (p 5 0.79). Results showed that the mean thyroid volume of normal thyroid function group (9.57 cm3) was significantly greater than that of the abnormal thyroid function group (8.06 cm3; p < 0.0001, Table 1). In addition, the mean thyroid echogeTABLE 1 Mean Characteristics of the Thyroid Glands on Sonography in Postradiotherapy Patients with Nasopharyngeal Carcinoma with Normal Thyroid Function versus Those with Abnormal Thyroid Function Mean 6 SD
Sonographic Appearance Thyroid volume (cm3) Echogenicity index Vascularity index Number of nodules TSH level (mIU/mL) fT4 level (pmol/L)
Normal Thyroid Function Group
Abnormal Thyroid Function Group
p Value*
9.57 6 2.60 2.32 6 0.88 29.64 6 11.31 0.45 6 0.82 2.55 6 0.99 11.35 6 1.53
8.06 6 2.39 2.03 6 0.99 29.28 6 12.14 0.58 6 0.86 9.32 6 9.87 8.67 6 1.50
