Clinical Predictors of Malignancy in Solitary Thyroid Nodule, A Study of 146 Cases

Ibrahim Falih Noori
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Keywords : Solitary thyroid nodule, malignancy, nodular goiter
Medical Journal of Babylon  14:1 , 2017 doi:1812-156X-14-1
Published :16 July 2017

Abstract

Although most of thyroid nodules are benign, 5-10% are malignant. It is important to predict the risk factors and malignant potential of STN to avoid unnecessary surgery with its complications. A prospective study was conducted to assess the rate and malignant potential of STN in 146 patients. They submitted to thorough investigations including a detailed history and clinical examination, thyroid function test, ultrasound examination and FNAC. There were 126 females and 20 males with female to male ratio about 6:1.The rate of malignancy in STNs was 8.9% with males affected more than female (15% Vs7.9%), and more with age above 40 in both sexes. History and clinical exam suspect malignancy in 6% of cases. All patients were euthyroid. Ultrasonic features such as Ill-defined margin, microclcifications, marked hypoechogenecity, and cervical lymphadenopathy are helpful features for prediction of malignancy, but none of these features are specific or pathognomonic. The results of FNAC in this study were:76 benign colloid goiter, 24 follicular tumor, 18 suspicious aspirate ,6 papillary carcinoma and 22 indeterminate cytology. The sensitivity , specificity and accuracy rate of FNAC in this study were 86.4%,96.3 and 92.3% respectively. History and examination are poor predictors of malignancy in STN. Male and increasing age are proved to be risk factors for malignancy in STN. Certain ultrasonic features are helpful in predicting malignancy but neither specific nor characteristics. These include ill-defined and irregular margin, microcalcification, marked hypoechogenecity, hyper-vascularity and cervical LAP. FNAC is highly sensitive in predicting malignant nodule. FNAC must be the first and could be the only test required to evaluate STN.

Introduction

Solitary thyroid nodule (STN) is referred as clinically discrete swelling in an otherwise impalpable gland. The estimated prevalence on the basis of palpation is about 4% to 7% of adults and increase by imaging to 20- 70%. About 50% of these nodules are turned to be part of multi-nodular and thus such nodules are termed dominant nodule [1]. Solitary thyroid nodules are commonly painless discovered incidentally, often noticed when the patient swallows. It affects about 6% of women and 2% of men with female to male ratio of 4:1. It is usually benign lesion [2]. The malignant potential of newly discovered thyroid nodule is of justifiable concern to both surgeon and patient and the main aim of investigation is to identify the relatively few patients with thyroid malignancy from the large proportion of patients with benign thyroid nodules. All malignant, suspicious nodules and large (3 or 4 cm) nodules usually mandate surgical intervention. The estimated incidence of malignancy in excised thyroid nodules is 8 to 17% [3]. The natural history of benign thyroid nodules is still unclear, but most palpable nodules probably reduce in size, with up to 38% disappearing completely [4,5]. The main concern with thyroid nodules is their potential risk of malignancy. Although thyroid malignancies are rare, constitute only 1%of all cancers in most populations and about 0.5% of all cancer death, the incidence of thyroid cancer in thyroid nodules regardless their size is about 5%-10% [4,6] The accurate prediction of malignancy in solitary thyroid nodule is very important to select the appropriate treatment and to avoid unnecessary extensive surgical procedures which may be associated with various surgical complications such as nerves injuries and hypothyroidism and hypoparathyroidism. We try in this study to investigate the clinical and pathological risk factors that could predict malignancy in solitary thyroid nodule and assess their application on the treatment plan. The aim of this study The objective of this study is to determine the incidence of thyroid cancer and predict the significant clinical and pathological risk factors of malignancy in patients presented with solitary thyroid nodule.

Materials and methods

This prospective study was carried out on 146 patients presented with apparently solitary thyroid nodule to the department of surgery in one major teaching hospital in Basra in a seven years period between   November 2008 and  August 2015 to assess the rate of malignancy, and investigate the clinical, imaging and pathological risk factors for  malignancy in these nodules. The inclusion criteria include all patients presented to surgical ward with solitary thyroid nodule. All Patients were euthyroid. Patients with clinical and biochemical evidence of thyrotoxicosis and hypothyroidism were excluded. Previous history of neck and head irradiation or family history of thyroid malignancy were  not recorded in this study.
The solitary thyroid nodule was a clinically single nodule of either lobes or isthmus  without any previous investigations that confirmed malignancy.
     All patients in this study were submitted to the same work up which includes clinical details such as age, sex, duration of symptoms, signs and symptom suggestive of hyperthyroidism, hypothyroidism and malignancy. Special emphasis was made regarding the rate of the growth of the lump, associated pain, any change in voice, pressure symptoms, any clinical evidence of thyrotoxicosis and presence of cervical lymphdenopathy. Family history of thyroid and other endocrine glands malignancy were also investigated.                                    The thyroid function test was estimated for all patients looking for any subclinical toxic adenoma.        
   All patients were referred for ultrasound examination. Neck ultrasound was done with 7.5-10 MHZ linear probe. The site, number, size, and the nature of nodule (cystic, solid and complex) were examined. Presence of microcalcifications cervical lymphadenopathy were determined also. Emphasis in ultrasound examination was on the nodules echogenecity and the margin characteristics including the presence or the absence of halo around the nodule. The echogenecity of each nodule was classified as hypoechoic, isoechoic, hyperechoic or mixed-echoic.                                                                                                                                             FNAC was performed to all patients by using 23G needle with standard technique by a single  expert cytopathologist. The results were classified as a benign simple colloid goiter,  malignant, suspicious, follicular tumor and indeterminate cytology.  Patients with  malignant, suspicious, follicular neoplasm and indeterminate aspirate were proceeded  for surgery. Besides, 28 patients with benign nodule subjected to surgery due to pressure symptoms or patients preference.  The type of surgery offered to the patients in this study were  hemithyroidectomy 
(lobectomy and isthmectomy), subtotal thyroidectomy and near total or total thyroidectomy according to each individual case. The total number of surgery performed  was 80 operations.




Results

There were 126 female and 20 male patients with age ranging from 22-67 year, mean age 44.3±4. Most these patients presented with asymptomatic anterior neck swelling discovered by the patient accidentally or by physician during routine clinical examination of unrelated health problem. Other less common symptoms were obstructive symptoms, change in the voice, and the presence of enlarged and palpable cervical lymph nodes The overall rate of malignancy of solitary thyroid nodules recorded in this study was 8.9% (13/146). There were 10 (8%) malignant thyroid nodules in the female patients and 3 (15%) in male patients. The incidence of malignancy was significantly higher among male patients (table 1). Females were predominant patients in this study, 126 females (86.3%), mean age 47.3±6 versus 20 males (13.7%), mean age 44.3±4, with male to female ratio of 6:1.The majority of the patients were in the late forties and fifties years of their life. Main presenting complaint was painless lower anterior neck swelling of different durations which are given by majority of the patients,(no. 117 patients, 80%). Other less frequent symptoms were obstructive symptoms such as shortness of breath and dysphagia observed in 10 (7%). hoarseness of voice was recorded in 6 (4%) and presence of painless enlarged cervical lymph node observed in 12 (8.2.%). (table2). The median duration of these swelling was 3.6 months. The results showed higher frequency of malignancy in solitary thyroid nodule in female patients above 40 years (8/60, 13.3%) than those below 40 years (2/66, 3.1%). The difference was significant (P>0.05). However, no such difference was encountered among male patients (1/6, 16.6%) patients below 40 years had malignancy compared to (2/14, 14.3%) in patients above 40 years. (table3). Of 18 cases clinically suspected to be malignant, only 5 cases were proved to be malignant by final histopathological examination. The clinical features that suggest malignancy were mainly hard and large nodule, change in the voice, and evidence of cervical lymphadenopathy. The average age of patients with malignant nodules was 50.7 years which was significantly higher than the average age of patient with benign nodules (34.3 years). Ultrasound was the main diagnostic tool which differentiate between the truly solitary nodules from dominant nodules (part of multinodular goiter), and according to ultrasonic findings, more nodules were in the right lobe near its junction with the isthmus followed by left lobe and isthmus. The size of the nodules measured by ultrasound range 1.5cm to 5.5 cm with mean of 2.8±3 cm. The studied nodules were proved to be solitary in 68 (46.6%) and dominant in 78 patients (53.4%). The frequency of malignancy was higher in true solitary nodules compared to dominant ones (61.5% in solitary nodules Vs. 38.5% in dominant) as shown in (table4). Features like, composition of the nodule, margin, microcalcifications, echogenecity, vascularity and evidence of cervical LAP were examined and detected. Regarding the nature of the nodules, 69 nodules appeared to be cystic, 71 nodules are solid and 6 nodules complex.. Eleven patients showed foci of microcalcifications which was mainly in solid and complex nodules. Regarding the echogenecity, 28 nodules were hypoechoic, 67 were hyperechoic, and the rest were isoechoic nodules. The presence of cervical lymphadenopathy were also looked for by ultrasound. It was detected in 12 patients, 5 of them prove to have malignancy in these enlarged nodes (Table 5). FNAC was the most crucial tool in the evaluation of thyroid nodules in this study. All patients in this study had FNAC examination either directly for palpable and large nodules or under ultrasound guidance for non palpable and small nodules.. The results showed that simple colloid goiter in 76 patients, follicular tumor in 24, suspicious aspirate in 18, papillary carcinoma in 6 cases and in the remaining 22 ,the results were indeterminate. Four patients with follicular tumor proved to be follicular carcinoma, and of those with indeterminate results, 3 cases proved to be papillary carcinoma by final histopathological exam. The total number of surgeries performed was 70 operations The types of surgery were lobectomy (35), subtotal thyroidectomy (26) and near total or total thyroidectomy (9). All the specimens were send for definite histopathological examination. Thyroid cancers proved to be found in `13 cases with papillary carcinoma was the most frequent type. None of the simple colloid goiter who are subjected to surgery showed malignancy. Histopathological findings in operated cases are shown in (table 6).

Discussions

Solitary thyroid nodule is defined as clinically discrete swelling in an otherwise impalpable remaining gland. Thyroid nodules are very common in clinical surgical practice with approximate prevalence that ranges from 4% to 7% by palpation, perhaps existing in almost half the population (50%), as determined by ultrasound and autopsy studies [2,7]. Thyroid nodule increase with age. Women have a higher prevalence than men. Spontaneous nodules occur in early childhood and extending into eighth decade of life [8]. The most common causes of thyroid nodule are simple colloid goiter, follicular adenoma, cysts and less frequently thyroiditis or could be dominant nodule of multinodular goiter . The main concern with thyroid nodules is their potential risk of malignancy. Although thyroid cancers are quite rare representing only 1% of all types of cancers and 0.5% of all cancer death, about 5% to 10% of solitary thyroid nodules are malignant[9]. The history of thyroid nodule is still unclear with some palpable thyroid nodules regressed and approximately up to 40% disappeared completely [10]. Because only small proportion of solitary thyroid nodules are malignant and since only malignant and symptomatic large nodules need surgery, the policy and the systemic approach for evaluation of these nodules are very important in order to avoid unnecessary surgery and its probable risks and complications. It is impractical to take a full history and perform a thorough clinical exam for every patient with solitary thyroid nodule and it is cost non effective to consume all available tests to predict the malignant potential of the nodule. Therefore, the main aim of solitary thyroid evaluation, is to select and treat those patients with malignant thyroid nodules surgically, while avoiding surgery with its risks and morbidity in patients with benign and painless nodules [11]. In our study, 13 of the 146 cases (8.9%) of solitary thyroid nodules were proved to be malignant. Most nodules were asymptomatic discovered accidentally by the patients, their relatives or by the physician when being examined for another problem. We found that the history is unhelpful in predicting the malignant potential of solitary thyroid nodule. Apart from a history of head and neck irradiation during childhood or early adolescent and family history of thyroid or other endocrine glands cancer, there are no specific points in the history is significantly associated with increased risk of malignancy[12].The history of sudden or progressive increase in the nodular size, pain, hoarseness or voice changes, and obstructive symptoms like dyspnea and dysphagia can occurs in both benign and malignant nodules [12,13]. Prior history of irradiation is unusual but, by far, is the greatest risk factors for thyroid cancer with estimated risk of malignancy in thyroid nodule of 35% to 40% compared to 5% in the general population. A positive family history of thyroid malignancy mainly medullary carcinoma of thyroid or other endocrine malignancy such a pheochromocytoma which should arise the suspicion of familial thyroid cancer or MEN 2 syndrome is also important [14]. None of our patients had a prior exposure to irradiation or family history of thyroid or other endocrine glands malignancies. Clinical examination can differentiate between solitary and dominant nodule in multinodular goiter. It is also of a limited help in distinguishing benign and malignant nodules except when there is a fixation or invasion of nearby structures in the neck and presence of palpable cervical lymph nodes. The size and consistency of the nodule are poor predictor of malignancy because they occur in both benign and malignant nodules. Obstructive symptoms like shortness of breath and stridor could also produced by benign lesion. Absent carotid pulsation due to carotid sheath invasion is highly suggestive of malignancy but this sign is rarely observed. [14,15]. In this study, malignancy was suspected in 18 cases with solitary thyroid nodule by clinical examination. Only 5 cases (27.7%) proved to be truly malignant. Cervical lymphadenopathy was evident in 3 patients proved to have a malignant papillary thyroid cancer. Fixation or invasion of nearby structures and absent carotid pulsation were not recorded in this study. Thyroid carcinomas are more frequent among females, but the incidence of malignancy is thought to be more common among male patients [4,16]. There was a significantly higher rate of malignancy in solitary thyroid nodules among male patients than in female patients in this study (15% Vs. 7.9% in females) and the majority of the patients proved to have a malignant nodule whether males or females were above 40 years (no.10, 76.9%). Table (2). The difference in the incidence of malignancy in the solitary thyroid nodule between both sexes and different age groups were both statistically significant (p< 0.05) So, male gender and increasing age in present study are considered as risk factor for malignancy in solitary thyroid nodules. These findings are in consistence with several similar studies [6,16,17,18] Assessment of thyroid functional status should be the initial steps in the work up and evaluation of thyroid nodules. Patients with malignant thyroid nodules are usually euthyroid, with less than 2% of nodules causing hyperthyroidism[1,5,19]. All patients with malignant solitary nodule in this study were euthyroid. Only 4 patients were discovered by investigation to have hyper-functioning thyroid nodules which proved to be benign by FNAC examination.. Ultrasound examinations were performed to all patients to determine the size, number, margin and composition of nodules, in addition to the presence of calcifications, and enlarged cervical lymph nodes. Ultrasound is safe, effective and non invasive investigation. Ultrasound can determine the presence of non palpable nodules as small as 1 to 2 mm size. The superiority of ultrasound examination of the thyroid over clinical examination was a subject of many studies before [19, 20]. A study by Marqusee et al [21] showed that ultrasound examination resulted in a change in the treatment of 44% of patients with a solitary thyroid nodule by physical examination. According to ultrasonic examination 56.2% of clinically apparent solitary thyroid nodules in present study were indeed dominant nodules of multinodular goiter. The incidence of malignancy was higher in solitary thyroid nodule (61.5% Vs. 38.5% in dominant nodules of multinodular goiter). The difference, however was not significant. Despite early belief that the dominant nodules are unlikely to be malignant, recent studies showed that the malignant potential in dominant nodule is similar to that in a solitary nodule [6,12]. Some studies emphasized that the incidence of malignancy is higher in solitary nodules than in multinodular goiter[4,11,18]. Other studies showed that patients with solitary thyroid nodules have the same risk of malignancy as those with multinodular goiter [3, 21], Hanumanthappa et al [22] recorded that the incidence of malignancy in multinodular goiter is quite significant and it is not very low as was thought. Accurate prediction of malignancy in thyroid nodules by ultrasound is usually difficult. Several studies have attempted to define which ultrasound characteristics are most predictive of malignancy [3, 23, 24, 25]. Up to date, no single features carries a high sensitivity, specificity and positive prediction for malignancy, However there are a number of ultrasound characteristics that when they occur in combination, could predict nodule with high malignant potential. These features include presence of punctate microcalcifications, evidence of cervical lymphadenopathy, large size nodule, solid component, an irregular or ill-defined margin, marked ,hypoechogenecity and hyper-vascularity [19, 26, 27]. Microcalcifications are psammoma bodies which are round laminar crystalline calcific deposit. These calcifications are most specific ultrasonic feature suggestive of malignancy with specificity of 85% to 95% and positive predictive value of 42% to 95% [12, 27, 28] Microcalcoficatios are detected in about 30% to 60% of all primary thyroid malignancies most frequently in papillary variant and less commonly in follicular and anaplastic types but could be also seen in benign lesions such as hyperplastic nodular goiter, Graves disease and lymphocytic thyroiditis [19,23,29]. Coarse calcifications occasionally detected with microcalcifications in papillary cancer and more commonly found in medullary carcinoma. Gopinathan et al, [30] stated in their review that when coarse calcifications is found in a solitary thyroid nodule, the risk of malignancy is as high as 75%. Microcalcifications were observed in 7 patients in this study, 6 of these cases proved to be papillary carcinoma and coarse calcifications were detected in 11 thyroid nodules, two of them proved to be malignant. Yuan et al [31] showed that the patterns of enhancement differ significantly between benign and malignant solitary thyroid nodules examined with real-time contrast-enhanced ultrasonography with most malignant nodule showing incomplete or heterogenous enhancement. Cervical lymphadenopathy and invasion of nearby structures are very specific and highly suggestive of thyroid malignancy but infrequently seen [32]. Ultrasonic features suspicious of lymph node metastasis include increased size, irregular margins, round bulging shape, heterogeneous echotexture and presence of calcifications [32, 33]. In present study cervical LAP was detected in 12 patients, 5 cases (41.7%) proved to malignant metastatic papillary carcinoma. Nodular size is not predictive of malignancy, and the risk for cancer in thyroid nodule has been shown to be the same regardless the size of the nodule [34]. Amitabh J et al, [35] and Tai et al. [11] showed in their studies that the size of nodule has no relation with the risk of malignancy. Same finding was observed in our study. Kamran et al [25] have a different opinion. They showed that the incidence of follicular cancer and other less frequent types of thyroid malignancies increase as the nodules enlarge. .

Conclusions

Although simple benign adenoma is the most common pathology of solitary thyroid nodule, about 5%-10% of these nodules are malignant. History and clinical exam are usually poor predictors of malignancy. Male gender, increasing age and evidence of cervical LAP were significantly associated with increased malignant potential in STN. Certain ultrasonic features are helpful in differentiating between benign and malignant nodules but none of these are pathognomonic or specific. These features are mainly ill-define margin, hypoechogenecity, microcalcifications hypervascularity of the nodule and the presence of cervical lymph adenopathy. FNAC has become the diagnostic test of choice for thyroid nodule. It is highly sensitive, specific and accurate in predicting malignant nodule in addition to be safe and cost effective. FNAC is advised to be the first and could be the only test required to evaluate thyroid nodule.

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