Solitary Thyroid Nodule High Incidence of Thyroid Cancer

The Aim: The preoperative distinguish between benign and malignant in solitary thyroid nodule is important. It helps to avoid unnecessary surgery and its adverse effects, such as hypothyroidism, hypocalcemia, and recurrent nerve injury. Methods: descriptive perspective analyzed data over a period of 6 years April 2015__April 2021 In Saudi hospital at Hajjah, Yemen. 226 thyroid operations for 207 patients ,135 patients diagnosis as Solitary thyroid nodule and 72 patients as Multi nodular goiter. the patients with a clinically as solitary thyroid nodule were included in the study group. Results: 135 cases of clinically detected STN,126 female and 9 male patients, between 14_65 years age, median 41 years and mean 39.76 years, (94 , 41)patients respectively Rt side thyroid effect more than Lt side, FNAC sensitivity, specicity and accuracy was (61% , 72% , 64%)respectively. Postoperative histopathology was reported 100(74%)patients as benign thyroid nodule and 35 patients(26%) as malignant thyroid nodule . Post operative transient hypocalcemia in 9 patients (7%), and temporary horsnese in 3 patients (2%). Conclusion: The incidence of malignancy in STN is high. Rapid growth by history and hard xed nodule by examination and hypoechoic, micro calcication and cervical lymphadenopathy on USG frequently in malignant nodules. Male risk factor for thyroid cancer while age, number and size of nodules were not. FNAC more helpful for diagnosis if aspiration under USG guide and reading by experience histopathologest .Type of surgery depending on preoperative evaluation including history, examination, ultrasound, FNAC result, and intraoperative assessment of the nodule .Less complications of thyroid surgery by experience surgeon.


Introduction
Solitary thyroid nodule is de ned clinically as a localized thyroid enlargement with an apparently normal remaining gland, refers to an abnormal growth of thyroid cells that forms a lump within the thyroid gland.
Although the vast majority of thyroid nodules are benign, a small proportion of thyroid nodules contain thyroid cancer. In order to diagnose and treat thyroid cancer at the earliest stage, most of thyroid nodules need some type of evaluation. Often these abnormal growths of thyroid tissue are located at the edge of the thyroid gland, so they can be felt as a lump in the front of neck. When they are large or when they occur in very thin individuals, they can even sometimes be seen as a lump in the front of the neck [1] .Thyroid nodules are common. Prevalence and incidence increases with age, with spontaneous nodules occurring at a rate of 0.08% per year beginning early in life and extending into the eighth decade.
Palpable Thyroid nodules are found in 5% of persons aged an average of 60 years. With the use of imaging techniques, particularly ultrasound, the chance of detection of thyroid nodules has increased many folds about 20%_60%. [2,3,4,5,6,7].
Thyroid nodules are more common in women than in men. [3,4,5,],its incidence in females is about one in 12-15 young women has a thyroid nodule, but in males is about one in 40 young men has a thyroid nodule. More than 95% of all thyroid nodules are benign (noncancerous growths). [4,5].
However, the reported incidence of thyroid cancer in general population is low, being only about 1%. Thyroid cancers occur in approximately 5_15% of all thyroid nodules independent of their size. [3,8] The recent data suggest that the incidence of thyroid malignancy is increasing over the years. [2,3],worldwide increase incidence of thyroid cancer partly due to increased detection by US and other imaging studies but also to true increase in incidence of papillary thyroid carcinoma (PTC). [9] The occurrence of malignancy is more in solitary thyroid nodules (STN) compared to multinodular goiter. [2,10,11].
The preoperative evaluation of thyroid nodules to distinguish between benign and malignant nodules is very important. It helps to avoid unnecessary extensive surgery and potential surgery related adverse effects, such as hypothyroidism, hypocalcemia, and recurrent laryngeal nerve injury. [2] Preoperative diagnoses were classi ed as benign, suspicious or malignant based on including history, clinical examination ndings (i.e. cervical lymphadenopathy, hoarseness of voice, presence of metastasis), thyroid function test, ultrasonographic features [12] and FNAC (The Bethesda system for reporting thyroid cytopathology). [13] The ultrasound the thyroid gland is used in differentiating the true solitary thyroid nodule from those with multinodular gland. Also it classi es the nodule into solid, cystic, or mixed. However it admit a little help in determining the pathological types of the nodule [14].
Fine-needle aspiration (FNA) cytology is the rst step that is performed to differentiate malignant nodules; however, 5-15% of FNA revealed inadequate nondiagnostic samples, and 15-30% of FNA result in indeterminate cytology ndings category III (atypia or follicular neoplasm of undetermined signi cance) and category IV (suspicious for follicular neoplasm) according to the Bethesda system [15,16].
Fine-needle aspiration cytology (FNA) is regarded as the rst diagnostic step to differentiate malignant from benign nodules. FNA has served with high accuracy to diagnose papillary thyroid carcinoma which accounts for 80%-90% of all thyroid cancer because papillary thyroid carcinoma has several speci c cytological nuclear features, such as optically clear elongated nuclei with nuclear grooves and intranuclear cytoplasmic pseudo inclusions [17,18,19] Fine-needle aspiration cytology (FNAC) has become the corner stone investigation. Unfortunately, on the basis of cytological characteristic alone, the pathologist cannot reliably distinguish benign from malignant follicular thyroid lesions, ∼20% of Fine-needle aspiration cytology (FNAC) will be given a nal diagnosis of follicular malignancy. [20].
For benign solitary nodule hemithyroidectomy of the involved lobe is recommended and not total thyroidectomy, but in treating suspicious and false-negative (FN), Fine-needle aspiration cytology (FNAC) reports could be overcome by total thyroidectomy, Hemithyroidectomy with or without isthmusectomy is performed as the initial operation for patients with an indeterminate cytological diagnosis and no clinical evidence of regional or distant metastatic disease or any other concurrent indication for total thyroidectomy. If gross extrathyroidal tumor extension or lymph node metastasis is found at the time of operation, a total thyroidectomy is then carried out [21].
The aim of the present study was to evaluate patients with clinically detected solitary thyroid nodule for the presence of malignancy, in relation to various factors like age, gender family history, rapid growth and clinical examination hard, xed nodule and ultrasonography (USG) ndings like size of the nodule, echogenicity, micro calci cation, and presence of lymphadenopathy,also Fine-needle aspiration cytology (FNAC) results. We also planned to compare the prevalence of malignancy in both solitary and multiple thyroid nodules detected by ultrasonography (USG).

Materials And Methods
This is a descriptive perspective analyzed our departmental data over a period of 6 years April 2015__April 2021. In Saudi hospital at Hajjah,Yemen. About 226 thyroid operations for 207 patients ,135 patients diagnosis as Solitary thyroid nodule and 72 patients as Multi nodular goiter All the patients who operated in surgical department with a clinically detected solitary thyroid nodule were included in the study group. Our approach was individualized as single team. Preoperative history, examination, thyroid function test , ultrasonography (USG) and ne-needle aspiration cytology were planned in all these patients. Hemi thyroidectomy and total thyroidectomy with and without neck dissection were performed wherever appropriate. The patients and their relatives gave consent to use the information for publication purpose. The study was approved by institutional ethics committee.
For all patients the following data were recorded: Age, gender, history of radiation exposure, family history of thyroid disease ,symptoms and growth rate of nodule , and the thyroid hormone pro le. The operative procedure was based on the different parameters like age of the patients, clinical examination, , Ultrasound interpretation, ne-needle aspiration cytology (FNAC) ndings and indirect laryngoscopy. The decision for surgery was based on individual patient's examination and investigation ndings.
In most of the patients, the plan of surgery was decided beforehand. If it was a solitary thyroid nodule, diagnosed clinically , ultrasonographically as well as ne-needle aspiration cytology (FNAC) as malignancy or high suspicion for malignancy proceed with total thyroidectomy. For others lower grad hemi-thyroidectomy of the involved side was done and the specimen was sent for routine histopathological examination (HPE). because inconclusive results no frozen section use , we preferred to wait till the nal histopathology report. If result of histopathological was positive for malignancy , completion thyroidectomy was done in 4_6 weeks , The decision for other procedures, total thyroidectomy with central neck dissection, total thyroidectomy with selective neck dissection, total thyroidectomy with modi ed radical neck dissection was based on the clinical, radiological, ne-needle aspiration cytology (FNAC) and histopathology ndings.
During surgery, the site and type of incision were decided. Hemostasis, safeguarding of the recurrent laryngeal nerve, parathyroid, and other vital structures was taken care of during the dissection. Appropriate measures were taken to correct postoperative hypocalcemia and care of the drain was taken . Further treatment plan was decided based on the nal histopathology report. If the report was benign, the patient was managed by regular monitoring of hormone levels, with or without thyroid hormone supplementation. Hypocalcemia features were managed with supplementation of calcium and Vitamin D.
If the nal histopathology report was either follicular or papillary carcinoma, the patients were advised to undergo I-131 whole body scan, preferably within 4-6 weeks after surgery and radioactive iodine ablation was advised for residual tissue in the thyroid bed. All the patients were advised regular follow-up one week, one month, 6months, one year, 2years. Before operation History and clinical examination done for all patients ,most common presentation of STN was as a swelling in the anterior aspect of the neck. The swelling was noticed by patient's relatives in most instances and in few cases, by patients themselves. Other less common symptoms were pain, hoarseness and dysphagia. The duration of symptoms ranged from one to 24 months. Rapid growth of nodule signi cantly last 3_6 month 20 cases, Family history of thyroid nodule was positive in 10 cases ,Hard nodule in 32 cases .
Laboratory tests including thyroid function test showed ( by FNAC 2 cases with Benign colloid nodule with compression symptoms, one case follicular neoplasia ,one case Hurthle cell neoplasia , one case suspicious categories, one case papillary thyroid cancer . benign solitary thyroid nodule appear in 3/6 (50%)patients, with hypothyroidism, All female, 2 Lt side and one Rt side .Result of histopathology was hashimotos thyroiditis in 2 cases and one case colloid goiter with hyperplastic nodule. After became euthyroid by medical treatment underwent surgery by total thyroidectomy in 2 cases and Rt hemithyroidectomy in one case.
Malignant Solitary thyroid nodule appeared 3/6 (50%) patients was hypothyroidism before operation, results of histopathology was malignant nodule as papillary thyroid cancer on background of hashimotos thyroiditis, one of them with lymph node metastasis. That's mean high risk for malignant transformation specially Papillary Thyroid cancer than lymphoma, after became euthyroid by hormonal replacement underwent to thyroid surgery as following.
Total thyroidectomy with central lymph nodes dissection in one patient, Total thyroidectomy with Rt lymph nodes dissection in one patient and was complicated by Temporary horsnese due to laryngeal edema that was improved during the rst month.
Rt hemithyroidectomy followed by completion Lt hemithyroidectomy with central lymph nodes dissection done in one patient. Should be noted that all patients received post operative thyroid hormones replacement, also should be noted not all cases hypothyroidism was hashimatous thyroiditis, as one case hypothyroidism and histopathology result was colloid goiter with hyperplastic nodule. hyperthyroidism appear in 4/100 patients All female with benign solitary thyroid nodule in the Rt side, histopathology result was 3 cases benign toxic adenoma And one case with colloid goiter hyperplastic nodule. After became euthyroid by medical treatment underwent surgery by total thyroidectomy, subtotal thyroidectomy, near total thyroidectomy and one case Rt hemithyroidectomy. That case post hemithyroidectomy become euthyroid follow up for 5years no recurrent until now and no received any replacement, but all other 3 cases received thyroid hormone therapy . 35
( Table 9) and (10)   20 patients with benign colloid goiter 4 of them with cystic degeneration and hyperplastic changes ,13 patients with benign adenomatous goiter 4 of them with cystic degenerative changes.
12 patients with benign hyperplastic nodular goiter 2 of them with cystic changes and marked brosis and calci cation. And one them with hyperplastic papillary nodule in benign nodular goiter, 5 patients with benign cystic nodule 3 of them with hemorrhagic cystic nodule and 2cases colloid cystic nodule, 7 patients with chronic thyroiditis (hashimotos and lymphocytes thyroiditis ),3 cases with hypothyroidism,3 patients with toxic adenoma and hyperthyroidism with average nodule size 4-5cm,28 patients with benign follicular adenoma 3 of them with lymphocytic thyroiditis and one case with cystic degenerative changes, 6 patients with benign hurthle cell adenoma (oncocystic neoplasm) and 6 patients with Non invasive follicular thyroid neoplasia with papillary nuclear like features (NIFTP) ,This type of thyroid tumor was previously classi ed non invasive encapsulated follicular variant of papillary thyroid cancer , but before few years reclassi ed this tumor as non malignant because character by absent capsular, vascular invasion ,tumor necrosis, high mitotic activity and have indolent behavior and may be over treatment if classify as type of cancer , All 6 patients was female ,between age 22_58 years ,mean 40.83 years ,median age 41 year, with standard deviation 12.38.

patients diagnosis as Lt Solitary thyroid nodule and 2 patients diagnosis as Rt Solitary thyroid nodule
and Average size 2_4 cm in 3 patients , 1_2cm in 1 patients and 4_5 cm in 2 patients ,Fine needle aspiration cytology benign cytology in 3 patient ,Follicular neoplasia in 2 patients and ,Suspicious nodule in 1 patients ,All 6 patients was euthyroid before operation, 3patients underwent Lt hemithyroidectomy and 2patients underwent Rt hemithyroidectomy.
as consider this term as benign not followed by total thyroidectomy ,only follow-up needed.
One patient underwent Total thyroidectomy because was in suspicious category ,One patient development post operative temporary horsnese was improved after few weeks .
In (Table 14

Management
Depending on the interpretation of the FNAB cytological specimen, management consists of observation, levothyroxine suppression therapy, or surgery.
Patients with benign solitary thyroid nodules may undergo observation or levothyroxine suppression therapy as the initial treatment modality. Levothyroxine is typically administered for 6-12 months to determine if the solitary thyroid nodule decreases in size. If the nodule decreases in size after treatment with levothyroxine, this medication is discontinued, with follow-up examination of the thyroid nodule in 3-6 months. However, if a benign solitary thyroid nodule increases in size, a repeat trial of levothyroxine and repeat FNAB may be indicated. Additionally, growth of a thyroid nodule during levothyroxine therapy is a strong indication for surgery.
No consensus exists regarding the degree of thyroid suppression or the e cacy of levothyroxine therapy. In fact, many endocrinologists no longer recommend thyroid suppression because of potential long-term adverse effects, such as osteoporosis and cardiac arrhythmias. Still others maintain a thyroid-stimulating hormone (TSH) level ranging from 0.1-0.3 mU/L rather than suppressing to the lowest limits of detectability to avoid immediate toxicity and long-term side effects. In (Table 16)

Discussion
Thyroid nodule refers to a localized lesion within the thyroid gland that is palpably or radiologically distinct from the surrounding thyroid parenchyma. [22].
Because high risk for malignant , surgeons tend to treat them with high degree of suspicion and plan treatment in a systematic manner. Clinically, STNs are common, being present in up to 50% of the elderly population. The majority of STNs are malignant. [ 2, 10 , 11] .
Therefore, it is recommended that all thyroid nodules >1 cm in size should undergo evaluation. This includes both palpable and nonpalpable nodules or detected by imaging. [ 22]. Thyroid nodules are more common in females similar as noted in the previous study. [ 2,6].
Solitary thyroid nodules were 10-11times more common in females as compared to males, [ 2,10], Our study showed that solitary thyroid nodules were 14 times more common in female than male. Further investigation should be considered if the following factors are present in addition to the thyroid nodule like male gender, extremes of age (<20 or >70 years), history of neck irradiation, nodule >4 cm in size or the presence of any pressure symptoms. [ 22] None of our patients in the study group had history of radiation exposure.
Patients under the age of 20 or over 70 years with thyroid nodules have an increased risk of malignancy, as do men. A history of persistent hoarseness, dysphagia, or dyspnea also increases the risk, although these symptoms may also occur with benign nodules. A rapid painless growth of a solid nodule is concerning and also raises the suspicion for thyroid cancer. [25].
Numerous studies have documented that the risk of malignancy in patients with thyroid nodules is 5%-17%, whether detected by palpation or ultrasonography.
There were 135 cases of clinically detected STN with available ultrasound ndings in the study group.
Thirty -ve (26%) (3:1)clinically detected STNs were reported as malignant in the nal HPE. This high incidence of malignancy reported in our study is similar to that of Tai et al. [ 2] . 36.6% (97) of the 265 patients and also reported 20%,42.27% incidence in the papers. [ 10,11] were proved to be malignant, which was higher than the general incidence of malignancy 5% .It seems that STN has a higher risk of malignancy, so in this condition we should focus on the potential danger to all these patients. The rise in incidence seems to be attributable both to the growing use of diagnostic imaging and neneedle aspiration biopsy, which has led to enhanced detection and diagnosis of subclinical nodules [52]and also early diagnosis of low-risk lesions [53].
The fact that the malignant percentages obtained in this study are higher is partly due to the pattern we used for selecting patients. In other words, we selected the cases from surgery wards, whereas other studies included in their experiments all the cases that were subjected to FNAC. As noted above, the risk of malignancy in this group has been reported to be 26% however, a higher rate has also been reported. [ 38,39,40].  (54)and Muratli et al., [ 38] reported that thyroid carcinoma prevalence was higher in the elderly compared with others while Rosario and et al. did not observe a signi cant difference between the age of the patients (55).Nevertheless, some studies including ours, revealed that the prevalence of thyroid carcinoma is higher in the younger patients [ 56,57].
In our study Most Solitary thyroid nodule even benign or malignant nodule take size between 2.1_4 Cm. Size of the nodule has no relation with the malignancy in our study which was also reported by Tai et al. [ 2] A study by Kamran et al. opined that the risk of follicular carcinomas and other rare thyroid malignancies increases as nodules enlarge. [ 27] However, no such association with size was seen in our cases.
Usually, the size of the thyroid nodule does not predict the likelihood of thyroid cancer. Only 8% of incidentally found thyroid nodules measuring <5 mm, 15% of nodules measuring 5-10 mm, and 13% of nodules measuring 10-15 mm are found to be malignant [24].
the results of this study revealed that the size of the thyroid nodules is not reliable at predicting malignancy and should not be applied in medical decision making. [ investigators also found the majority of malignant tumors in both size groups to be low-risk lesions. [ 45].
In our study(72%,63%) Rt side thyroid more effected by either benign or malignant solitary thyroid nodules respectively. Was similar to study by Liechty et al 9 noticed that there was a predilection for benign and malignant nodules to occur in the right lobe and Robinson et al 1 also found that in 40% cases the nodules were located in the right lobe. [60].
Malignant Solitary thyroid nodule appeared 3/6 (50%) patients was hypothyroidism before operation, results of histopathology was malignant nodule as papillary thyroid cancer on background of hashimotos thyroiditis, one of them with lymph node metastasis. That's mean high risk for malignant transformation specially Papillary Thyroid cancer than lymphoma, [ 50].
Ultrasonography is the most cost-effective imaging procedure, and is highly sensitive in assessing nodule size and number. There are ultrasound patterns which suggest malignancy like irregular shape, ill-de ned borders, hypoechogenicity, solid texture, heterogeneous internal echoes, micro calci cation, absence of a halo, an anteroposterior to transverse diameter ratio (A/T) >1, in ltration into regional structures, and suspicious regional lymph nodes. [ 22].
Thyroid ultrasonography can be helpful in certain cases when it is used to guide FNAB. Data have suggested that ultrasonography-guided FNAB may be preferable to palpation-guided FNAB. [61] Ultrasound may aid in localization and examination of nodules, but FNA or excisional biopsy is necessary to de nitively determine presence of malignancy [62].
addition, high resolution ultrasound and ancillary testing in the form of molecular genetics and immunocytochemistry can improve diagnostic accuracy. [ 41][63].
The likelihood that the increased incidence of thyroid cancer being largely be related to early detection by high resolution ultrasound and discovery of sub-clinical thyroid nodules. [63 ][ 64 ] is supported by evidence suggesting survival rates for thyroid cancer have remained fairly stable. [ 65].
In our study 28 patients out of a total 35(80%) malignant case had micro calci cation by thyroid ultrasound in contrast to 10 of 100 (10%)benign nodules, This nding suggests that in presence of micro calci cation, the incidence of malignancy is more similar to study by Kuo et al indicated that on ultrasonographic examination, the presence of calci cation within a thyroid lesion, nodule-like solid masses are independent factors for thyroid cancer specially follicular thyroid carcinoma instead of a follicular adenoma. [ 47]. Also similar to An article by Rago et al. suggested that atypia at cytology and spot micro calci cation at ultrasound was predictive of malignancy [29].
Presence of solid echogenicity contributes to increased incidence of malignancy in comparison to either cystic or mixed echogenicity of the nodule. According to literature, STN has a higher risk of malignancy than multiple nodules. [ 2] .
Male gender, normal thyroid volume, single nodularity, nodule hypo echogenicity, and blurred margins were also associated with malignancy but size not signi cantly [29] .
We have noted that male gender, micro calci cation, solid echogenicity of the nodule, and presence of cervical lymphadenopathy was signi cantly associated with malignancy similar as noted by Tai et al. [ 2]. study by Yuan et al, however, indicated that the patterns of enhancement differ signi cantly between benign and malignant solitary thyroid nodules examined with real-time, contrast-enhanced ultrasonography, with most malignant lesions in the report demonstrating an irregular shape, an unclear boundary, and inhomogeneous and incomplete enhancement. The study involved 78 patients, including 41 with benign lesions and 37 with malignant nodules. [ 46 ] Desjardins et al found that one half of their patients with thyroid carcinoma had a cystic component in the tumor. [ 49 ].
ne-needle aspiration biopsy (FNAB) has become the most important tool in the assessment of solitary thyroid nodules. [ 43 ].
Fine-needle aspiration cytology is recommended to be a cost-effective procedure in the initial assessment and management of thyroid nodules. [2,11] It is recommended that every patient with a palpable thyroid nodule should undergo an FNAC. USG-guided FNAC can lower the occurrence of nondiagnostic smears.
Whenever we had problem in preoperative diagnosis by FNAC due to inadequate material or di culty in aspiration by conventional method we have repeated the FNAC by USG guidance. In our study and previous study experience also noted, better yield of diagnostic cytological material with the help of the USG-guided aspirations compared to blind FNAC. [ 31,32].
All our patients underwent FNAC by ultrasound guide before surgery as it helped us to decide the type of surgery to be under taken. When FNAC report was malignant or suspicious , total thyroidectomy was done. In all other cases, hemi thyroidectomy was done and subsequent plan was decided based on conclusive para n section report.
In a recent article, the authors have emphasized the role of USG by suggesting that nodules with a nondiagnostic FNAC result in the setting of low-risk demographics and benign appearance at ultrasound can be followed with serial ultrasound examinations, thereby avoiding repeat FNAC. [ 33] These ndings are in contrast to the recommended current guidelines to repeat FNAC after a nondiagnostic result. [ 62].
Determining the nature of STN is very important as aggressive surgery may be regarded as an excessive mode of treatment. [ 2] We opted for surgery in all the patients as there is a high incidence of malignancy in STN patients as reported in literature. [ 2] The postoperative histopathology reports corroborated our ndings as nearly ~1/3 of STN were reported as malignant.
study by Arul and  The sensitivity of FNA cytology in this study is low compared to published studies from outside country where The sensitivity, speci city and accuracy of FNA cytology are more than 94%. which had adversely affected the surgical decision making as well as the outcome. We should realise that negative FNA cytology does not exclude malignancy and we have to seriously evaluate the situation and to rethink on how to raise the scale of sensitivity in FNA cytology in the diagnosis of thyroid nodules, and to improve the level of expertise in cytology.
Yemen, as any developing country, is lacking an accepted level of expertise in this eld, something that makes it mandatory to continuously monitor and evaluate how valid this procedure is. whose study reported . However, this high rate of malignancy is not surprising if we know that FNAC is nowadays routinely performed for most cases of thyroid nodules. This has led to a reduction in the number of unnecessary surgeries and consequently to a rise in the percentage reported for malignancy. [ 39].
In our study risk of malignancy for each Bethesda category in following       Table 8 Fine needle aspiration cytology results according to the Bethesda Categories with its subtypes.     Table 13 Solitary Thyroid Nodule post operation Histopathology Results [ Table 16].
Type of surgical neck dissection