Clinical Imaging 38 (2014) 621–626
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Ultrasound of primary thyroid non-Hodgkin's lymphoma☆ Buyun Ma a, Yiping Jia b,⁎, Qian Wang c, Xinxiao Li d a
Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, China Department of Ultrasound, West China Fourth Hospital, Sichuan University, Chengdu, China c Department of Hematology, West China Hospital, Sichuan University, Chengdu, China d Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chengdu, China b
a r t i c l e
i n f o
Article history: Received 19 January 2012 Received in revised form 9 April 2012 Accepted 13 April 2012 Keywords: Thyroid tumor Primary Non-Hodgkin's lymphoma Ultrasonography High-frequency ultrasound
a b s t r a c t Objective: The aim of this study was to review the high-frequency ultrasonography findings of primary thyroid non-Hodgkin's lymphoma (PT-NHL). Methods: Data of 39 patients treated for PT-NHL and 48 patients as controls were retrospectively reviewed. Results: The mean age of patients, Hashimoto's thyroiditis, marked hypoechogenicity of the lesion, asymmetrical enlargement of the thyroid, cervical lymph node enlargement, enhancement of posterior echoes, and linear echogenic septations were all more statistically significantly different in the PT-NHL group than in the control group. Conclusion: Ultrasonographic characteristics predictive of PT-NHL are marked hypoechogenicity in the lesion and asymmetrical enlargement of the thyroid gland. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Lymphoma is a common hematopoietic malignancy that typically involves lymph nodes and/or extranodal lymphoid tissues. Primary thyroid Hodgkin's lymphoma is rarely found in clinical practice, whereas primary thyroid non-Hodgkin's lymphoma (PT-NHL) accounts for 1.3%–2.5% of thyroid cancers and approximately 0.5% of lymphomas [1–3]. Thyroid lymphoma is frequently found in middle-aged and elderly women, and as many as 70%–90% of patients with thyroid lymphoma have concomitant Hashimoto's thyroiditis [3,4]. PT-NHL typically manifests as a rapidly developing cervical mass that compresses the surrounding tissues and organs, resulting in dyspnea and dysphagia [2,3,5,6]. Fine-needle aspiration biopsy (FNAB) under ultrasound guidance is the initial procedure of choice for the histopathological diagnosis of thyroid diseases [7–9]. FNAB has also been found useful in the diagnosis of primary lymphoma of the thyroid, although the diagnostic accuracy is not as high as for other conditions of the thyroid [10–12]. High-frequency ultrasound (HFUS) is simple and noninvasive, can identify lesions in superficial tissues and organs, and currently plays an important role in the screening, preoperative diagnosis,
☆ Conflict of interest: None to declare. ⁎ Corresponding author. No. 18 Renmin Nanlu Road Section 3, Chengdu, Sichuan Province 610041, China. Tel.: +86 2885502089. E-mail address: [email protected] (Y. Jia). http://dx.doi.org/10.1016/j.clinimag.2012.04.024 0899-7071/© 2014 Elsevier Inc. All rights reserved.
and postoperative follow-up of thyroid diseases [7,13–16]. However, few studies have reported the use and diagnostic value of HFUS with respect to thyroid lymphoma. The purpose of the retrospective study was to analyze the sonographic characteristics of PT-NHL and the predictive value of these findings. 2. Materials and methods 2.1. Patients From May 2002 to December 2008, 39 patients with PT-NHL were treated at West China Hospital, Sichuan University, Chengdu, China, and included in this retrospective study. In addition, 48 patients with thyroid diseases other than PT-NHL treated at our hospital from June 2005 to April 2009 were selected at random and included as the control group. All patients received HFUS examinations and had complete records of the ultrasonography results and histopathological data. This study was approved by the institutional review board of our hospital, and because of the retrospective nature of the study, the requirement for informed patient consent was waived. Ultrasound examinations were performed by a physician experienced in thyroid ultrasound with an Acuson Sequoia 512 (Siemens Healthcare, Mountain View, CA, USA), ATL HDI 5000 (ATL, Bothell, WA, USA), or a Philips IU22 (Philips Medical Systems, Best, the Netherlands) with a linear probe with a frequency of 7.5–12 MHz. For examinations, patients were in a supine position with their
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neck extended. Transverse, longitudinal, and oblique images were obtained. Ultrasound images of the PT-NHL patients and controls were analyzed by another physician experienced in thyroid ultrasound who was not aware of the final diagnosis but had other clinical data including medical history, symptoms, and laboratory results available. This was done because when seeing a patient, a physician obtains a medical history, examines clinical manifestations, and obtains laboratory data and imaging data in order to make a diagnosis. Thus, having the medical records would not bias the diagnosis made by ultrasound. The examining physician recorded the following ultrasonographic findings: (1) the presence of Hashimoto's thyroiditis (based on imaging findings), (2) whether the boundary between the lesion and surrounding tissues was clear, (3) whether marked hypoechogenicity (an echo intensity lower than that of the thyroid gland or absence of echo) in the lesion was presented, (4) whether the lesion was irregular, (5) whether there was an asymmetric enlargement of the thyroid, (6) the presence of tissue liquefaction (defined as an echoless area in the mass), (7) extent of vascular supply to the lesion, (8) the presence of calcifications (micro and/or macro), (9) enlargement of cervical lymph nodes, (10) the presence of echo enhancement behind the lesion, and (11) the presence of linear echogenic septations in the lesion. An ultrasonography diagnosis of PT-NHL was based on the presence of marked hypoechogenicity of the lesion with concomitant Hashimoto's thyroiditis plus asymmetric enlargement of the thyroid. The sonographic criteria used for a diagnosis of Hashimoto's thyroiditis were enlarged or normal volume of the thyroid gland, echo reduction in the gland, and diffuse net/cord-like echo enhancement. If the subject was female and there was enlargement of the cervical lymph nodes, the diagnosis can be more affirmative. Of the case group, pathological diagnoses were achieved by surgical specimens and/or histopathological examination of FNAB (i.e., 21-gauge biopsy). PT-NHL was classified according to the World Health Organization criteria [17]. The rationale for subject selection in the control group was as follows: most thyroid lymphomas originate from Hashimoto's thyroiditis. Especially in patients without an obvious mass, this disease is usually misdiagnosed as Hashimoto's thyroiditis. To validate the feasibility of ultrasound in the diagnosis of thyroid lymphoma, patients with Hashimoto's thyroiditis (n=26) accounted for more than 50% of subjects in the control group. In addition, thyroid lymphoma is usually characterized by a mass-like shape, and the mass is often large. Thus, some patients with large masses that were malignant were also recruited as controls. If subjects in the control group were randomly selected (most of patients had no lesion, a fraction of patients had benign lesions, and a fraction of patients had malignant lesions), the feasibility of ultrasound in the detection of thyroid lymphoma would be high due to selection bias. 2.2. Statistical analysis The continuous variable, age, was summarized as mean±standard deviation, and the independent two-sample t test was performed to compare the differences in age between the PT-NHL and control groups. Disease duration, another continuous variable, was nonnormally distributed, and data were summarized as median with interquartile range. The Mann-Whitney test was performed to compare the differences between the groups. All other categorical variables were presented by count and percentage and were compared with Fisher's Exact Test. Univariate and multivariate logistic regression models were used to investigate the factors associated with a diagnosis of PT-NHL and were summarized by odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Variables that obtained statistical significance in the univariate analysis (Pb.05) were selected by the forward conditional stepwise method and were analyzed in the multivariate model. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the multivariate model. All statistical
analyses were performed with SPSS 15.0 statistical software (SPSS Inc., Chicago, IL, USA), and a P value b.05 was considered to indicate statistical significance.
3. Results 3.1. Patient characteristics Patient demographic and clinical data are presented in Table 1. There was no difference in the distribution of gender between the two groups, while the mean age of patients with PT-NHL was significantly greater than that of the control group (62.2 years vs. 41.1 years, respectively; Pb.001). Significantly longer disease duration before seeking help was observed in the PT-NHL group as compared to the control group (6.0 vs. 2.0 months, respectively; Pb.001). The PT-NHL group had a significantly greater incidence of dysphagia (53.8% vs. 27.1%, P=.015), hoarseness (25.6% vs. 6.3%, P=.016), and dyspnea (23.1% vs. 4.2%, respectively; P=.010) than the control group. Among the 39 PT-NHL patients (30 were female, 9 were male), marginal zone B-cell lymphoma was found in 22 (partial cell transformation in 10 patients), diffuse large B-cell lymphoma in 12, follicular lymphoma in 1, Burkitt's lymphoma in 1, and unclassified lymphoma in 3. Based on the criteria of Ota et al. [13], in the current study, 15 PT-NHLs were of nodular type, 19 were of diffuse type, and 5 were of mixed type. Analysis revealed that the risk of PT-NHL in patients ≥ 60 years of age was 7.4 times higher than that in patients in the control group (Pb.05). Ten patients had involvement of the cervical lymph nodes, and 36 had concomitant Hashimoto's thyroiditis. The mean size of the tumors was 6.1 cm (range, 2.4–13.3 cm). Lesions were found in the right lobe (n= 10), left lobe (n= 12), right lobe and isthmus (n=3), left lobe and isthmus (n=1), whole thyroid (n= 12), and isthmus only (n= 1). In the control group of 48 patients (44 were female, 4 were male), there were 22 thyroid carcinomas (17 papillary carcinomas, 2 follicular carcinomas, 2 medullary carcinomas, 1 oncocytic adenoma) and 26 cases of Hashimoto's thyroiditis.
Table 1 Comparison of patient demographic, clinical, and ultrasonographic characteristics
Age (years) Gender Male Female Disease duration before seeking help (months) Symptoms Dysphagia Hoarseness Dyspnea Superior vena cava syndrome HFUS findings Hashimoto's thyroiditis Well-defined lesion margin Marked hypoechogenicity of the lesion Irregular lesion shape Asymmetric enlargements of right and left glands (right and left halves/lobes of the gland) Liquefaction Hypervascular Presence of calcifications (micro and/or macro) Cervical lymph node enlargement Enhancement of posterior echoes Linear echogenic septations ⁎ Pb.05.
Control group (n=48)
PT-NHL group (n=39)
P
41.1±16.1
62.2±13.4
b.001⁎
4 (8.3%) 44 (91.7%) 2.0 (1.0-4.0)
9 (23.1%) 30 (76.9%) 6.0 (3.0-10.0)
13 (27.1%) 3 (6.3%) 2 (4.2%) 0 (0.0%)
21 (53.8%) 10 (25.6%) 9 (23.1%) 3 (7.7%)
26 (54.2%) 34 (70.8%) 11 (22.9%) 11 (22.9%) 4 (8.3%)
36 31 37 10 28
(92.3%) (79.5%) (94.9%) (25.6%) (71.8%)
b.001⁎ .459 b.001⁎
7 (14.6%) 40 (83.3%) 16 (33.3%)
1 (2.6%) 29 (74.4%) 4 (10.3%)
.069 .425 .020⁎
13 (27.1%) 26 (54.2%) 21 (43.8%)
21 (53.8%) 33 (84.6%) 30 (76.9%)
.015⁎ .003⁎ .002⁎
.072 b.001⁎ .015⁎ .016⁎ .010⁎ .086
.805 b.001⁎
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Fig. 1. Marginal zone B-cell lymphoma with asymmetrical enlargement of the thyroid. A relatively small right lobe (A) and a markedly enlarged left lobe (B) are seen.
Ultrasonographic findings of the two groups are presented in Table 1. Hashimoto's thyroiditis (92.3% vs. 54.2%, Pb.001), marked hypoechogenicity of the lesion (94.9% vs. 22.9%, Pb.001), asymmetrical enlargement of the right and left glands (71.8% vs. 8.3%, Pb.001), cervical lymph node enlargement (53.8% vs. 27.1%, P=.015), enhancement of posterior echoes (84.6% vs. 54.2%, P=.003), and linear echogenic septations (76.9% vs. 43.8%, P=.002) were all significantly greater in the PT-NHL group than in the control group. The presence of calcifications, however, was significantly lower in the PT-NHL group than in the control group (10.3% vs. 33.3%, respectively; P=.020) (Table 1). Representative ultrasound images are shown in Figs. 1–3.
was markedly hypoechogenic were more likely to have PT-NHL than those without marked hypoechogenicity of the lesion (OR, 26.12; 95% CI, 4.17–163.51; Pb.001), and patients with asymmetrical enlargement of the right and left glands (right and left halves/lobes of the gland) were more likely to have PT-NHL than those without asymmetrical enlargement (OR, 10.84; 95% CI, 2.26–52.07; P=.003). In addition, a slight increase in the risk of having PT-NHL was noted with an increase of age (OR, 1.06; 95% CI, 1.01–1.12; P=.010). The multivariate model was evaluated using the ROC curve analysis, as shown in Fig. 4. The AUC was 0.950, with a 95% CI of 0.902–0.998, which indicated good performance of the multivariate model.
3.2. Factors associated with PT-NHL
3.3. Ultrasonographic features diagnostic of PT-NHL
In the univariate logistic regression model, 12 variables were found to be significantly associated with PT-NHL: age, disease duration before seeking help, dysphagia, hoarseness, dyspnea, Hashimoto's thyroiditis, marked hypoechogenicity of the lesion, asymmetrical enlargement of the right and left glands (right and left halves/lobes of the gland), the presence of calcifications, cervical lymph node enlargement, enhancement of posterior echoes, and linear echogenic septations (Table 2). However, only three variables with the most significant impact on the diagnosis of PT-NHL—age, marked hypoechogenicity of the lesion, and asymmetrical enlargement of right and left glands (right and left halves/lobes of the gland) —were selected as input into the multivariate logistic regression model. Multivariate analysis indicate that patients in whom the lesion
Because two features identified with HFUS—marked hypoechogenicity of the lesion and asymmetrical enlargement of the right and left glands—had significant impacts on the diagnosis of PT-NHL in the multivariate model, four diagnostic combinations were compared: marked hypoechogenicity (method 1), asymmetrical enlargement of the right and left thyroids (method 2), marked hypoechogenicity or asymmetrical enlargement of the right and left thyroids (method 3), and marked hypoechogenicity and asymmetrical enlargement of the right and left thyroids (method 4) (Table 3). The AUC for method 3 was the greatest (0.875), followed by 0.860 for method 1. The corresponding sensitivity, specificity, positive predictive value, and negative predictive value were 1, 0.750, 0.765, and 1, respectively, for method 3 and 0.949, 0.771, 0.771, and 0.949, respectively,
Fig. 2. Illustration of a false-negative case (marginal zone B-cell lymphoma with concomitant Hashimoto's thyroiditis. (A) An adenoma-like node presented as a well-defined lesion with hypervascularity and relatively even echogenicity in the left lobe. (B) Concomitant Hashimoto's thyroiditis was too minor to be indentified in ultrasound images, although pathology examination confirmed that most of the thyroid gland was involved by Hashimoto's thyroiditis.
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Fig. 3. Illustration of a false-positive case. A large lesion with marked hypoechogenicity was confirmed to be medullary thyroid carcinoma on histopathological examination. Fig. 4. ROC curve for the prediction result by the multivariate logistic regression model. AUC=0.950; 95% CI, 0.902–0.998; Pb.001.
for method 1. These results indicate that marked hypoechogenicity and asymmetrical enlargement of the right and left thyroid are highly predictive of PT-NHL. 4. Discussion PT-NHL responds differently from other lymphomas to treatments, and it can be difficult to differentiate from poorly differentiated thyroid carcinomas clinically and histologically [3,5,6]. Thus, accurate and timely diagnosis is crucial to improve outcomes. In this study of the ultrasonographic characteristics of PT-NHL, we found that marked hypoechogenicity and asymmetrical enlargement of the thyroid were predictive of PT-NHL. Progressive development of a cervical mass is the most common symptom of PT-NHL patients, which is usually accompanied by dysphagia, hoarseness, dyspnea, and superior vena cava syndrome, and when compared with malignancies of the thyroid, patients with PT-NHL present with a relatively larger mass [2,3,5,6]. All patients in our study with PT-NHL presented with a cervical mass N 2.0 cm in
diameter, and asymmetrical enlargement of the thyroid gland was common. We also found dysphagia, hoarseness, and dyspnea to be more common in the PT-NHL group; however, the average age of the PT-NHL patients (62.2 years) was markedly greater than that of the control group (41.1 years), and the greater frequency of these symptoms may be related to the greater age of the PT-NHL patients rather than the disease itself. Cervical lymph node enlargement due to lymphoma may be different from lymphadenopathy due to other thyroid malignancies. Enlarged cervical lymph nodes due to lymphoma are usually larger and greater in number than with other types of malignancy, the aspect ratio (longer dimension: shorter dimension) is markedly imbalanced (rounder), the lymphatic portal is reduced or absent, internal echoes are reduced or absent, and blood perfusion is of mixed type, that is, both central and peripheral perfusion. For reactive hyperplasia, the aspect ratio of the enlarged lymph nodes is usually N 2, internal echo reduction is not as great as in lymphomas, the lymph node cortex and portal both are visible with clear demarcation, and blood
Table 2 Results of univariate and multivariate logistic regression models for factors associated with a diagnosis of PT-NHL Univariate OR (95% CI) Age (years) Disease duration before seeking help (months) Gender (male vs. female) Symptoms Dysphagia Hoarseness Dyspnea HFUS findings Hashimoto's thyroiditis Well-defined lesion margin Marked hypoechogenicity of the lesion Irregular lesion shape Asymmetric enlargement of right and left glands (right and left halves/lobes of the gland) Liquefaction Hypervascular Presence of calcification Cervical lymph node enlargement Enhancement of posterior echoes Linear echogenic septations
Multivariate P
OR (95% CI)
1.10 (1.06-1.15) 1.30 (1.12-1.50) 3.30 (0.93-11.70)
b.001⁎ .001⁎ .065
1.06 (1.01-1.12)
3.14 (1.28-7.69) 5.17 (1.31-20.40) 6.90 (1.39-34.17)
.012⁎ .019⁎ .018⁎
10.15 (2.75-37.54) 1.60 (0.59-4.32) 62.23 (12.89-300.32) 1.16 (0.43-3.11) 28.00 (8.11-96.62)
b.001⁎ .358 b.001⁎ .768 b.001⁎
0.15 0.58 0.23 3.14 4.65 4.29
(0.02-1.31) (0.20-1.65) (0.07-0.76) (1.28-7.69) (1.65-13.15) (1.68-10.95)
P .010⁎
26.12 (4.17-163.51)
b.001⁎
10.84 (2.26-52.07)
.003⁎
.087 .307 .016⁎ .012⁎ .004⁎ .002⁎
Data regarding superior vena cava syndrome was not available for the logistic regression model and not included in the table. Variables found to have statistical significance in the univariate model were selected into the multivariate model by the forward conditional stepwise method. The other variables were not selected into the multivariate model because they were not independent factors. ⁎ Pb.05 indicates that the corresponding variable had a significant impact on the risk of PT-NHL.
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Table 3 Predictive value of marked hypoechogenicity and asymmetrical enlargement of thyroid for PT-NHL
Method Method Method Method
1 2 3 4
Markedly hypoechogenic Asymmetric enlargement of right and left glands Markedly hypoechogenic or asymmetric enlargement of right and left glands Markedly hypoechogenic and asymmetric enlargement of right and left glands
AUC (95% CI)
P
Sensitivity
Specificity
PPV
NPV
0.860 0.817 0.875 0.802
b.001* b.001* b.001* b.001*
0.949 0.718 1.000 0.667
0.771 0.917 0.750 0.938
0.771 0.875 0.765 0.897
0.949 0.800 1.000 0.776
(0.777-0.943) (0.720-0.914) (0.797-0.953) (0.702-0.902)
PPV, positive predictive value; NPV, negative predictive value.
perfusion is central. For metastasis to the lymph nodes, the nodes are enlarged with the imbalanced aspect ratio, internal echo reduction is not as great as in lymphomas, the internal structure is damaged, the lymph node portal structure is absent or there is evidence of invasion, and blood perfusion is peripheral. Imaging modalities used in the diagnosis of thyroid disease, as well as of the head and neck, include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) [14–18]. While CT and MRI play a role in the diagnosis and staging of thyroid cancer, ultrasonography and FNAB have been proven to be the most efficient first-line method for the diagnosis of thyroid diseases [7,8,16,19]. Based on ultrasonographic tumor boundaries and echoes in and behind the tumor, Ota et al. [13] classified thyroid lymphoma into three types: nodular, diffuse, and mixed. Nodular-type PT-NHL is usually confined to a unilateral lobe, and the boundary between the tumor and surrounding tissue is very clear. Diffuse-type PT-NHL usually involves two lobes, and the lesion has no clear boundary, which makes differentiating diffuse-type PT-NHL and severe chronic thyroiditis difficult. Mixed-type PT-NHL is characterized by multiple patchy lesions with hypoechoic regions in the thyroid. In the same report by Ota et al. [13], the authors found that an enhanced echo behind the lesion was specific for all thyroid lymphomas. Our results were inconsistent with their findings; that is, our results indicated that HFUS findings specific for a diagnosis of PT-HNL were marked hypoechogenicity in the lesion and asymmetrical enlargement of the right and left glands. The discrepancies may be because (1) only patients with suspected lymphoma by ultrasonography were included in their study, and thus, there was bias in the patient selection, and (2) controls were not included in their study. In present study, 26 patients with PT-NHL had concomitant Hashimoto's thyroiditis, and Hashimoto's thyroiditis is characterized by the hyperplasia of lymphoid tissues, which also results in a hypoechogenicity in the lesion and enhanced echogenicity behind the lesion. Kwak et al. [10] studied six patients with primary thyroid lymphoma and also reported that the most notable ultrasonographic characteristic of thyroid lymphoma was marked hypoechogenicity of the mass compared with the surrounding tissue. While color Doppler and high-frequency ultrasonography have been shown to be extremely effective for visualization of the thyroid and diagnosis, histopathological examination of a tissue specimen is usually required for a definitive diagnosis [7,8,16]. Because patients who develop PT-NHL usually have concomitant Hashimoto's thyroiditis, some researchers have speculated that Hashimoto's thyroiditis can activate B cells to secrete autoantibodies, resulting in hyperplasia or malignant transformation of lymphoid tissue [3,4]. In a report of 10 patients with PT-NHL, Wirtzfeld et al. [2] reported that 70% had a history of Hashimoto's thyroiditis. In the present study, a majority of patients (92.3%) with PT-NHL also had Hashimoto's thyroiditis, which is consistent with previous reports in which from approximately 30% to 90% of patients with PT-NHL had Hashimoto's thyroiditis [1,2,4,13,20–23]. Interestingly, in a study of 1652 patients with Graves' disease and 2036 with Hashimoto's thyroiditis, Mukasa et al. [24] found that the prevalence of papillary thyroid carcinoma was significantly higher in patients with Hashimoto's thyroiditis and in those with Graves' disease, and two patients with Hashimoto's thyroiditis were found to have malignant
lymphoma. Due to the significant correlation with malignancy, Hashimoto's thyroiditis is considered a precancerous condition by some authors [24,25]. In addition, some studies have reported an important role of gene mutation in the occurrence of PT-NHL [20,26]. Furthermore, PT-NHL is more common in females than in males and frequently occurs in middle-aged or elderly women [1,2,4,13]. In the present study, the mean age of PT-NHL patients was 62 years, the female-to-male ratio was 3:1, and the risk ratio of PT-NHL in patients ≥ 60 years old was 7.4 times higher than in the control group. While the presence of Hashimoto's thyroiditis can make diagnosis of other benign and malignant thyroid conditions more difficult, Anderson et al. [18] reported that the sonographic appearance of benign and malignant nodules in patients with diffuse Hashimoto's thyroiditis is generally similar to that of benign and malignant nodules in individuals without Hashimoto's. FNAB is an important strategy in the primary diagnosis of PT-NHL. A majority of PT-NHL can be confirmed by FNAB, and surgical biopsy can be avoided [11,27]. Although needle aspiration biopsy is a simple and convenient method for the primary diagnosis, the differentiation of lymphoma from undifferentiated carcinoma and that of low-grade lymphoma from Hashimoto's thyroiditis are difficult [5]. Moreover, the histological classification is difficult because of inadequate specimens [2,28]. With ultrasound guidance, multiple biopsies of a mass or suspicious lesion can be performed, which may decrease false-negative rate and avoid surgical biopsy confirmation. The prognosis of PT-NHL is closely related to the pathological types and clinical stages, especially the tumor size and the extent of cancer invasion. The 5-year survival rate in patients with low malignant potential is as high as 100%, but in those with moderate or high malignant potential, survival is relatively poor [6,29]. A 5-year survival rate of 64% can be reached if the lesion is confined to the thyroid, while the prognosis of PT-NHL with extrathyroidal invasion is extremely poor [4,30]. Although early diagnosis of PT-NHL is a critical factor of prognosis, unfortunately, most patients with PT-NHL present with a late stage of the disease because of poor knowledge and awareness of the malignancy by most interpreting clinicians. There are two limitations of this study that should be considered. The first limitation is its retrospective nature, and the second is the relatively small number of patients. However, primary thyroid lymphoma is a relatively rare disease, and it is difficult to perform a prospective study and obtain a large number of cases for analysis. In summary, ultrasonographic characteristics predictive of PT-NHL are marked hypoechogenicity in the lesion and asymmetrically enlargement of the thyroid gland. Even in patients without nodules, an asymmetrically enlarged lobe should arouse suspicion of PT-NHL, especially in patients with Hashimoto's thyroiditis. The use of HFUS may improve the diagnostic accuracy of PT-NHL, lead to earlier diagnosis, and reduce the need for surgical biopsies to arrive at a diagnosis.
Acknowledgments The study was accomplished with the support of the Department of Ultrasound, West China Hospital. The authors would like to thank Professor Juying Zhang and Qian Jiang for excellent statistical support.
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Ultrasound of primary thyroid non-Hodgkin's lymphoma☆ Buyun Ma a, Yiping Jia b,⁎, Qian Wang c, Xinxiao Li d a
Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, China Department of Ultrasound, West China Fourth Hospital, Sichuan University, Chengdu, China c Department of Hematology, West China Hospital, Sichuan University, Chengdu, China d Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chengdu, China b
a r t i c l e
i n f o
Article history: Received 19 January 2012 Received in revised form 9 April 2012 Accepted 13 April 2012 Keywords: Thyroid tumor Primary Non-Hodgkin's lymphoma Ultrasonography High-frequency ultrasound
a b s t r a c t Objective: The aim of this study was to review the high-frequency ultrasonography findings of primary thyroid non-Hodgkin's lymphoma (PT-NHL). Methods: Data of 39 patients treated for PT-NHL and 48 patients as controls were retrospectively reviewed. Results: The mean age of patients, Hashimoto's thyroiditis, marked hypoechogenicity of the lesion, asymmetrical enlargement of the thyroid, cervical lymph node enlargement, enhancement of posterior echoes, and linear echogenic septations were all more statistically significantly different in the PT-NHL group than in the control group. Conclusion: Ultrasonographic characteristics predictive of PT-NHL are marked hypoechogenicity in the lesion and asymmetrical enlargement of the thyroid gland. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Lymphoma is a common hematopoietic malignancy that typically involves lymph nodes and/or extranodal lymphoid tissues. Primary thyroid Hodgkin's lymphoma is rarely found in clinical practice, whereas primary thyroid non-Hodgkin's lymphoma (PT-NHL) accounts for 1.3%–2.5% of thyroid cancers and approximately 0.5% of lymphomas [1–3]. Thyroid lymphoma is frequently found in middle-aged and elderly women, and as many as 70%–90% of patients with thyroid lymphoma have concomitant Hashimoto's thyroiditis [3,4]. PT-NHL typically manifests as a rapidly developing cervical mass that compresses the surrounding tissues and organs, resulting in dyspnea and dysphagia [2,3,5,6]. Fine-needle aspiration biopsy (FNAB) under ultrasound guidance is the initial procedure of choice for the histopathological diagnosis of thyroid diseases [7–9]. FNAB has also been found useful in the diagnosis of primary lymphoma of the thyroid, although the diagnostic accuracy is not as high as for other conditions of the thyroid [10–12]. High-frequency ultrasound (HFUS) is simple and noninvasive, can identify lesions in superficial tissues and organs, and currently plays an important role in the screening, preoperative diagnosis,
☆ Conflict of interest: None to declare. ⁎ Corresponding author. No. 18 Renmin Nanlu Road Section 3, Chengdu, Sichuan Province 610041, China. Tel.: +86 2885502089. E-mail address: [email protected] (Y. Jia). http://dx.doi.org/10.1016/j.clinimag.2012.04.024 0899-7071/© 2014 Elsevier Inc. All rights reserved.
and postoperative follow-up of thyroid diseases [7,13–16]. However, few studies have reported the use and diagnostic value of HFUS with respect to thyroid lymphoma. The purpose of the retrospective study was to analyze the sonographic characteristics of PT-NHL and the predictive value of these findings. 2. Materials and methods 2.1. Patients From May 2002 to December 2008, 39 patients with PT-NHL were treated at West China Hospital, Sichuan University, Chengdu, China, and included in this retrospective study. In addition, 48 patients with thyroid diseases other than PT-NHL treated at our hospital from June 2005 to April 2009 were selected at random and included as the control group. All patients received HFUS examinations and had complete records of the ultrasonography results and histopathological data. This study was approved by the institutional review board of our hospital, and because of the retrospective nature of the study, the requirement for informed patient consent was waived. Ultrasound examinations were performed by a physician experienced in thyroid ultrasound with an Acuson Sequoia 512 (Siemens Healthcare, Mountain View, CA, USA), ATL HDI 5000 (ATL, Bothell, WA, USA), or a Philips IU22 (Philips Medical Systems, Best, the Netherlands) with a linear probe with a frequency of 7.5–12 MHz. For examinations, patients were in a supine position with their
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neck extended. Transverse, longitudinal, and oblique images were obtained. Ultrasound images of the PT-NHL patients and controls were analyzed by another physician experienced in thyroid ultrasound who was not aware of the final diagnosis but had other clinical data including medical history, symptoms, and laboratory results available. This was done because when seeing a patient, a physician obtains a medical history, examines clinical manifestations, and obtains laboratory data and imaging data in order to make a diagnosis. Thus, having the medical records would not bias the diagnosis made by ultrasound. The examining physician recorded the following ultrasonographic findings: (1) the presence of Hashimoto's thyroiditis (based on imaging findings), (2) whether the boundary between the lesion and surrounding tissues was clear, (3) whether marked hypoechogenicity (an echo intensity lower than that of the thyroid gland or absence of echo) in the lesion was presented, (4) whether the lesion was irregular, (5) whether there was an asymmetric enlargement of the thyroid, (6) the presence of tissue liquefaction (defined as an echoless area in the mass), (7) extent of vascular supply to the lesion, (8) the presence of calcifications (micro and/or macro), (9) enlargement of cervical lymph nodes, (10) the presence of echo enhancement behind the lesion, and (11) the presence of linear echogenic septations in the lesion. An ultrasonography diagnosis of PT-NHL was based on the presence of marked hypoechogenicity of the lesion with concomitant Hashimoto's thyroiditis plus asymmetric enlargement of the thyroid. The sonographic criteria used for a diagnosis of Hashimoto's thyroiditis were enlarged or normal volume of the thyroid gland, echo reduction in the gland, and diffuse net/cord-like echo enhancement. If the subject was female and there was enlargement of the cervical lymph nodes, the diagnosis can be more affirmative. Of the case group, pathological diagnoses were achieved by surgical specimens and/or histopathological examination of FNAB (i.e., 21-gauge biopsy). PT-NHL was classified according to the World Health Organization criteria [17]. The rationale for subject selection in the control group was as follows: most thyroid lymphomas originate from Hashimoto's thyroiditis. Especially in patients without an obvious mass, this disease is usually misdiagnosed as Hashimoto's thyroiditis. To validate the feasibility of ultrasound in the diagnosis of thyroid lymphoma, patients with Hashimoto's thyroiditis (n=26) accounted for more than 50% of subjects in the control group. In addition, thyroid lymphoma is usually characterized by a mass-like shape, and the mass is often large. Thus, some patients with large masses that were malignant were also recruited as controls. If subjects in the control group were randomly selected (most of patients had no lesion, a fraction of patients had benign lesions, and a fraction of patients had malignant lesions), the feasibility of ultrasound in the detection of thyroid lymphoma would be high due to selection bias. 2.2. Statistical analysis The continuous variable, age, was summarized as mean±standard deviation, and the independent two-sample t test was performed to compare the differences in age between the PT-NHL and control groups. Disease duration, another continuous variable, was nonnormally distributed, and data were summarized as median with interquartile range. The Mann-Whitney test was performed to compare the differences between the groups. All other categorical variables were presented by count and percentage and were compared with Fisher's Exact Test. Univariate and multivariate logistic regression models were used to investigate the factors associated with a diagnosis of PT-NHL and were summarized by odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Variables that obtained statistical significance in the univariate analysis (Pb.05) were selected by the forward conditional stepwise method and were analyzed in the multivariate model. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the multivariate model. All statistical
analyses were performed with SPSS 15.0 statistical software (SPSS Inc., Chicago, IL, USA), and a P value b.05 was considered to indicate statistical significance.
3. Results 3.1. Patient characteristics Patient demographic and clinical data are presented in Table 1. There was no difference in the distribution of gender between the two groups, while the mean age of patients with PT-NHL was significantly greater than that of the control group (62.2 years vs. 41.1 years, respectively; Pb.001). Significantly longer disease duration before seeking help was observed in the PT-NHL group as compared to the control group (6.0 vs. 2.0 months, respectively; Pb.001). The PT-NHL group had a significantly greater incidence of dysphagia (53.8% vs. 27.1%, P=.015), hoarseness (25.6% vs. 6.3%, P=.016), and dyspnea (23.1% vs. 4.2%, respectively; P=.010) than the control group. Among the 39 PT-NHL patients (30 were female, 9 were male), marginal zone B-cell lymphoma was found in 22 (partial cell transformation in 10 patients), diffuse large B-cell lymphoma in 12, follicular lymphoma in 1, Burkitt's lymphoma in 1, and unclassified lymphoma in 3. Based on the criteria of Ota et al. [13], in the current study, 15 PT-NHLs were of nodular type, 19 were of diffuse type, and 5 were of mixed type. Analysis revealed that the risk of PT-NHL in patients ≥ 60 years of age was 7.4 times higher than that in patients in the control group (Pb.05). Ten patients had involvement of the cervical lymph nodes, and 36 had concomitant Hashimoto's thyroiditis. The mean size of the tumors was 6.1 cm (range, 2.4–13.3 cm). Lesions were found in the right lobe (n= 10), left lobe (n= 12), right lobe and isthmus (n=3), left lobe and isthmus (n=1), whole thyroid (n= 12), and isthmus only (n= 1). In the control group of 48 patients (44 were female, 4 were male), there were 22 thyroid carcinomas (17 papillary carcinomas, 2 follicular carcinomas, 2 medullary carcinomas, 1 oncocytic adenoma) and 26 cases of Hashimoto's thyroiditis.
Table 1 Comparison of patient demographic, clinical, and ultrasonographic characteristics
Age (years) Gender Male Female Disease duration before seeking help (months) Symptoms Dysphagia Hoarseness Dyspnea Superior vena cava syndrome HFUS findings Hashimoto's thyroiditis Well-defined lesion margin Marked hypoechogenicity of the lesion Irregular lesion shape Asymmetric enlargements of right and left glands (right and left halves/lobes of the gland) Liquefaction Hypervascular Presence of calcifications (micro and/or macro) Cervical lymph node enlargement Enhancement of posterior echoes Linear echogenic septations ⁎ Pb.05.
Control group (n=48)
PT-NHL group (n=39)
P
41.1±16.1
62.2±13.4
b.001⁎
4 (8.3%) 44 (91.7%) 2.0 (1.0-4.0)
9 (23.1%) 30 (76.9%) 6.0 (3.0-10.0)
13 (27.1%) 3 (6.3%) 2 (4.2%) 0 (0.0%)
21 (53.8%) 10 (25.6%) 9 (23.1%) 3 (7.7%)
26 (54.2%) 34 (70.8%) 11 (22.9%) 11 (22.9%) 4 (8.3%)
36 31 37 10 28
(92.3%) (79.5%) (94.9%) (25.6%) (71.8%)
b.001⁎ .459 b.001⁎
7 (14.6%) 40 (83.3%) 16 (33.3%)
1 (2.6%) 29 (74.4%) 4 (10.3%)
.069 .425 .020⁎
13 (27.1%) 26 (54.2%) 21 (43.8%)
21 (53.8%) 33 (84.6%) 30 (76.9%)
.015⁎ .003⁎ .002⁎
.072 b.001⁎ .015⁎ .016⁎ .010⁎ .086
.805 b.001⁎
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Fig. 1. Marginal zone B-cell lymphoma with asymmetrical enlargement of the thyroid. A relatively small right lobe (A) and a markedly enlarged left lobe (B) are seen.
Ultrasonographic findings of the two groups are presented in Table 1. Hashimoto's thyroiditis (92.3% vs. 54.2%, Pb.001), marked hypoechogenicity of the lesion (94.9% vs. 22.9%, Pb.001), asymmetrical enlargement of the right and left glands (71.8% vs. 8.3%, Pb.001), cervical lymph node enlargement (53.8% vs. 27.1%, P=.015), enhancement of posterior echoes (84.6% vs. 54.2%, P=.003), and linear echogenic septations (76.9% vs. 43.8%, P=.002) were all significantly greater in the PT-NHL group than in the control group. The presence of calcifications, however, was significantly lower in the PT-NHL group than in the control group (10.3% vs. 33.3%, respectively; P=.020) (Table 1). Representative ultrasound images are shown in Figs. 1–3.
was markedly hypoechogenic were more likely to have PT-NHL than those without marked hypoechogenicity of the lesion (OR, 26.12; 95% CI, 4.17–163.51; Pb.001), and patients with asymmetrical enlargement of the right and left glands (right and left halves/lobes of the gland) were more likely to have PT-NHL than those without asymmetrical enlargement (OR, 10.84; 95% CI, 2.26–52.07; P=.003). In addition, a slight increase in the risk of having PT-NHL was noted with an increase of age (OR, 1.06; 95% CI, 1.01–1.12; P=.010). The multivariate model was evaluated using the ROC curve analysis, as shown in Fig. 4. The AUC was 0.950, with a 95% CI of 0.902–0.998, which indicated good performance of the multivariate model.
3.2. Factors associated with PT-NHL
3.3. Ultrasonographic features diagnostic of PT-NHL
In the univariate logistic regression model, 12 variables were found to be significantly associated with PT-NHL: age, disease duration before seeking help, dysphagia, hoarseness, dyspnea, Hashimoto's thyroiditis, marked hypoechogenicity of the lesion, asymmetrical enlargement of the right and left glands (right and left halves/lobes of the gland), the presence of calcifications, cervical lymph node enlargement, enhancement of posterior echoes, and linear echogenic septations (Table 2). However, only three variables with the most significant impact on the diagnosis of PT-NHL—age, marked hypoechogenicity of the lesion, and asymmetrical enlargement of right and left glands (right and left halves/lobes of the gland) —were selected as input into the multivariate logistic regression model. Multivariate analysis indicate that patients in whom the lesion
Because two features identified with HFUS—marked hypoechogenicity of the lesion and asymmetrical enlargement of the right and left glands—had significant impacts on the diagnosis of PT-NHL in the multivariate model, four diagnostic combinations were compared: marked hypoechogenicity (method 1), asymmetrical enlargement of the right and left thyroids (method 2), marked hypoechogenicity or asymmetrical enlargement of the right and left thyroids (method 3), and marked hypoechogenicity and asymmetrical enlargement of the right and left thyroids (method 4) (Table 3). The AUC for method 3 was the greatest (0.875), followed by 0.860 for method 1. The corresponding sensitivity, specificity, positive predictive value, and negative predictive value were 1, 0.750, 0.765, and 1, respectively, for method 3 and 0.949, 0.771, 0.771, and 0.949, respectively,
Fig. 2. Illustration of a false-negative case (marginal zone B-cell lymphoma with concomitant Hashimoto's thyroiditis. (A) An adenoma-like node presented as a well-defined lesion with hypervascularity and relatively even echogenicity in the left lobe. (B) Concomitant Hashimoto's thyroiditis was too minor to be indentified in ultrasound images, although pathology examination confirmed that most of the thyroid gland was involved by Hashimoto's thyroiditis.
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Fig. 3. Illustration of a false-positive case. A large lesion with marked hypoechogenicity was confirmed to be medullary thyroid carcinoma on histopathological examination. Fig. 4. ROC curve for the prediction result by the multivariate logistic regression model. AUC=0.950; 95% CI, 0.902–0.998; Pb.001.
for method 1. These results indicate that marked hypoechogenicity and asymmetrical enlargement of the right and left thyroid are highly predictive of PT-NHL. 4. Discussion PT-NHL responds differently from other lymphomas to treatments, and it can be difficult to differentiate from poorly differentiated thyroid carcinomas clinically and histologically [3,5,6]. Thus, accurate and timely diagnosis is crucial to improve outcomes. In this study of the ultrasonographic characteristics of PT-NHL, we found that marked hypoechogenicity and asymmetrical enlargement of the thyroid were predictive of PT-NHL. Progressive development of a cervical mass is the most common symptom of PT-NHL patients, which is usually accompanied by dysphagia, hoarseness, dyspnea, and superior vena cava syndrome, and when compared with malignancies of the thyroid, patients with PT-NHL present with a relatively larger mass [2,3,5,6]. All patients in our study with PT-NHL presented with a cervical mass N 2.0 cm in
diameter, and asymmetrical enlargement of the thyroid gland was common. We also found dysphagia, hoarseness, and dyspnea to be more common in the PT-NHL group; however, the average age of the PT-NHL patients (62.2 years) was markedly greater than that of the control group (41.1 years), and the greater frequency of these symptoms may be related to the greater age of the PT-NHL patients rather than the disease itself. Cervical lymph node enlargement due to lymphoma may be different from lymphadenopathy due to other thyroid malignancies. Enlarged cervical lymph nodes due to lymphoma are usually larger and greater in number than with other types of malignancy, the aspect ratio (longer dimension: shorter dimension) is markedly imbalanced (rounder), the lymphatic portal is reduced or absent, internal echoes are reduced or absent, and blood perfusion is of mixed type, that is, both central and peripheral perfusion. For reactive hyperplasia, the aspect ratio of the enlarged lymph nodes is usually N 2, internal echo reduction is not as great as in lymphomas, the lymph node cortex and portal both are visible with clear demarcation, and blood
Table 2 Results of univariate and multivariate logistic regression models for factors associated with a diagnosis of PT-NHL Univariate OR (95% CI) Age (years) Disease duration before seeking help (months) Gender (male vs. female) Symptoms Dysphagia Hoarseness Dyspnea HFUS findings Hashimoto's thyroiditis Well-defined lesion margin Marked hypoechogenicity of the lesion Irregular lesion shape Asymmetric enlargement of right and left glands (right and left halves/lobes of the gland) Liquefaction Hypervascular Presence of calcification Cervical lymph node enlargement Enhancement of posterior echoes Linear echogenic septations
Multivariate P
OR (95% CI)
1.10 (1.06-1.15) 1.30 (1.12-1.50) 3.30 (0.93-11.70)
b.001⁎ .001⁎ .065
1.06 (1.01-1.12)
3.14 (1.28-7.69) 5.17 (1.31-20.40) 6.90 (1.39-34.17)
.012⁎ .019⁎ .018⁎
10.15 (2.75-37.54) 1.60 (0.59-4.32) 62.23 (12.89-300.32) 1.16 (0.43-3.11) 28.00 (8.11-96.62)
b.001⁎ .358 b.001⁎ .768 b.001⁎
0.15 0.58 0.23 3.14 4.65 4.29
(0.02-1.31) (0.20-1.65) (0.07-0.76) (1.28-7.69) (1.65-13.15) (1.68-10.95)
P .010⁎
26.12 (4.17-163.51)
b.001⁎
10.84 (2.26-52.07)
.003⁎
.087 .307 .016⁎ .012⁎ .004⁎ .002⁎
Data regarding superior vena cava syndrome was not available for the logistic regression model and not included in the table. Variables found to have statistical significance in the univariate model were selected into the multivariate model by the forward conditional stepwise method. The other variables were not selected into the multivariate model because they were not independent factors. ⁎ Pb.05 indicates that the corresponding variable had a significant impact on the risk of PT-NHL.
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Table 3 Predictive value of marked hypoechogenicity and asymmetrical enlargement of thyroid for PT-NHL
Method Method Method Method
1 2 3 4
Markedly hypoechogenic Asymmetric enlargement of right and left glands Markedly hypoechogenic or asymmetric enlargement of right and left glands Markedly hypoechogenic and asymmetric enlargement of right and left glands
AUC (95% CI)
P
Sensitivity
Specificity
PPV
NPV
0.860 0.817 0.875 0.802
b.001* b.001* b.001* b.001*
0.949 0.718 1.000 0.667
0.771 0.917 0.750 0.938
0.771 0.875 0.765 0.897
0.949 0.800 1.000 0.776
(0.777-0.943) (0.720-0.914) (0.797-0.953) (0.702-0.902)
PPV, positive predictive value; NPV, negative predictive value.
perfusion is central. For metastasis to the lymph nodes, the nodes are enlarged with the imbalanced aspect ratio, internal echo reduction is not as great as in lymphomas, the internal structure is damaged, the lymph node portal structure is absent or there is evidence of invasion, and blood perfusion is peripheral. Imaging modalities used in the diagnosis of thyroid disease, as well as of the head and neck, include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) [14–18]. While CT and MRI play a role in the diagnosis and staging of thyroid cancer, ultrasonography and FNAB have been proven to be the most efficient first-line method for the diagnosis of thyroid diseases [7,8,16,19]. Based on ultrasonographic tumor boundaries and echoes in and behind the tumor, Ota et al. [13] classified thyroid lymphoma into three types: nodular, diffuse, and mixed. Nodular-type PT-NHL is usually confined to a unilateral lobe, and the boundary between the tumor and surrounding tissue is very clear. Diffuse-type PT-NHL usually involves two lobes, and the lesion has no clear boundary, which makes differentiating diffuse-type PT-NHL and severe chronic thyroiditis difficult. Mixed-type PT-NHL is characterized by multiple patchy lesions with hypoechoic regions in the thyroid. In the same report by Ota et al. [13], the authors found that an enhanced echo behind the lesion was specific for all thyroid lymphomas. Our results were inconsistent with their findings; that is, our results indicated that HFUS findings specific for a diagnosis of PT-HNL were marked hypoechogenicity in the lesion and asymmetrical enlargement of the right and left glands. The discrepancies may be because (1) only patients with suspected lymphoma by ultrasonography were included in their study, and thus, there was bias in the patient selection, and (2) controls were not included in their study. In present study, 26 patients with PT-NHL had concomitant Hashimoto's thyroiditis, and Hashimoto's thyroiditis is characterized by the hyperplasia of lymphoid tissues, which also results in a hypoechogenicity in the lesion and enhanced echogenicity behind the lesion. Kwak et al. [10] studied six patients with primary thyroid lymphoma and also reported that the most notable ultrasonographic characteristic of thyroid lymphoma was marked hypoechogenicity of the mass compared with the surrounding tissue. While color Doppler and high-frequency ultrasonography have been shown to be extremely effective for visualization of the thyroid and diagnosis, histopathological examination of a tissue specimen is usually required for a definitive diagnosis [7,8,16]. Because patients who develop PT-NHL usually have concomitant Hashimoto's thyroiditis, some researchers have speculated that Hashimoto's thyroiditis can activate B cells to secrete autoantibodies, resulting in hyperplasia or malignant transformation of lymphoid tissue [3,4]. In a report of 10 patients with PT-NHL, Wirtzfeld et al. [2] reported that 70% had a history of Hashimoto's thyroiditis. In the present study, a majority of patients (92.3%) with PT-NHL also had Hashimoto's thyroiditis, which is consistent with previous reports in which from approximately 30% to 90% of patients with PT-NHL had Hashimoto's thyroiditis [1,2,4,13,20–23]. Interestingly, in a study of 1652 patients with Graves' disease and 2036 with Hashimoto's thyroiditis, Mukasa et al. [24] found that the prevalence of papillary thyroid carcinoma was significantly higher in patients with Hashimoto's thyroiditis and in those with Graves' disease, and two patients with Hashimoto's thyroiditis were found to have malignant
lymphoma. Due to the significant correlation with malignancy, Hashimoto's thyroiditis is considered a precancerous condition by some authors [24,25]. In addition, some studies have reported an important role of gene mutation in the occurrence of PT-NHL [20,26]. Furthermore, PT-NHL is more common in females than in males and frequently occurs in middle-aged or elderly women [1,2,4,13]. In the present study, the mean age of PT-NHL patients was 62 years, the female-to-male ratio was 3:1, and the risk ratio of PT-NHL in patients ≥ 60 years old was 7.4 times higher than in the control group. While the presence of Hashimoto's thyroiditis can make diagnosis of other benign and malignant thyroid conditions more difficult, Anderson et al. [18] reported that the sonographic appearance of benign and malignant nodules in patients with diffuse Hashimoto's thyroiditis is generally similar to that of benign and malignant nodules in individuals without Hashimoto's. FNAB is an important strategy in the primary diagnosis of PT-NHL. A majority of PT-NHL can be confirmed by FNAB, and surgical biopsy can be avoided [11,27]. Although needle aspiration biopsy is a simple and convenient method for the primary diagnosis, the differentiation of lymphoma from undifferentiated carcinoma and that of low-grade lymphoma from Hashimoto's thyroiditis are difficult [5]. Moreover, the histological classification is difficult because of inadequate specimens [2,28]. With ultrasound guidance, multiple biopsies of a mass or suspicious lesion can be performed, which may decrease false-negative rate and avoid surgical biopsy confirmation. The prognosis of PT-NHL is closely related to the pathological types and clinical stages, especially the tumor size and the extent of cancer invasion. The 5-year survival rate in patients with low malignant potential is as high as 100%, but in those with moderate or high malignant potential, survival is relatively poor [6,29]. A 5-year survival rate of 64% can be reached if the lesion is confined to the thyroid, while the prognosis of PT-NHL with extrathyroidal invasion is extremely poor [4,30]. Although early diagnosis of PT-NHL is a critical factor of prognosis, unfortunately, most patients with PT-NHL present with a late stage of the disease because of poor knowledge and awareness of the malignancy by most interpreting clinicians. There are two limitations of this study that should be considered. The first limitation is its retrospective nature, and the second is the relatively small number of patients. However, primary thyroid lymphoma is a relatively rare disease, and it is difficult to perform a prospective study and obtain a large number of cases for analysis. In summary, ultrasonographic characteristics predictive of PT-NHL are marked hypoechogenicity in the lesion and asymmetrically enlargement of the thyroid gland. Even in patients without nodules, an asymmetrically enlarged lobe should arouse suspicion of PT-NHL, especially in patients with Hashimoto's thyroiditis. The use of HFUS may improve the diagnostic accuracy of PT-NHL, lead to earlier diagnosis, and reduce the need for surgical biopsies to arrive at a diagnosis.
Acknowledgments The study was accomplished with the support of the Department of Ultrasound, West China Hospital. The authors would like to thank Professor Juying Zhang and Qian Jiang for excellent statistical support.
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