|Year : 2014 | Volume
| Issue : 1 | Page : 28-32
The association between serum thyroid-stimulating hormone concentration and development of differentiated thyroid cancers in nodular thyroid disease
Mohammad Arafat, Sameh Gabr, Ibrahim A Ghaffar, Ahmad A Rahman, Zakaria Hamza, Ahmad A Fattah, Mohammad A Fattah, Mohammad Mira
Department of General Surgery, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
|Date of Submission||01-Oct-2013|
|Date of Acceptance||15-Oct-2013|
|Date of Web Publication||22-Jul-2014|
Ibrahim A Ghaffar
Department of General Surgery, Faculty of Medicine, Al-Azhar University, Cairo
Source of Support: None, Conflict of Interest: None
To evaluate the relation between serum thyroid-stimulating hormone (TSH) and development of differentiated thyroid cancers in nodular thyroid disease (NTD) in Egyptians.
Patients and methods
One hundred patients were included in this study at Al-Azhar University Hospitals from 2010 to 2013; all patients with NTD, who were fit for surgery, were selected for study. The preoperative TSH level was estimated and was compared with the final histopathological diagnosis for the presence of malignant thyroid lesions.
A total of 100 patients were included in the study, with an average age of 46 years. The male to female ratio was 1 : 4.7. Seventy-five patients had multinodular goiter, whereas 25 patients had a solitary thyroid nodule. Eighty-six patients underwent total thyroidectomy, whereas 14 patients underwent near- total thyroidectomy. The final histopathological data showed no evidence of malignancy in 83 patients, 83% (benign group), whereas malignant lesions were present in 17 patients, 17% (malignant group). The preoperative mean TSH level in the benign group was 1.72 ± 1.4 mIU/L, whereas the mean TSH concentration in the malignant group was 2.61 ± 2.2 mIU/l.
There is a definite relation between serum TSH and development of differentiated thyroid cancers in NTD as the risk of thyroid malignancy increases with increased serum TSH concentrations.
Keywords: nodular thyroid disease, thyroid cancer, thyroid-stimulating hormone
|How to cite this article:|
Arafat M, Gabr S, Ghaffar IA, Rahman AA, Hamza Z, Fattah AA, Fattah MA, Mira M. The association between serum thyroid-stimulating hormone concentration and development of differentiated thyroid cancers in nodular thyroid disease. J Arab Soc Med Res 2014;9:28-32
|How to cite this URL:|
Arafat M, Gabr S, Ghaffar IA, Rahman AA, Hamza Z, Fattah AA, Fattah MA, Mira M. The association between serum thyroid-stimulating hormone concentration and development of differentiated thyroid cancers in nodular thyroid disease. J Arab Soc Med Res [serial online] 2014 [cited 2017 Oct 19];9:28-32. Available from: http://www.new.asmr.eg.net/text.asp?2014/9/1/28/137322
| Introduction|| |
About 4-7% of the population has thyroid nodules ; this range depends on differences in iodine nutrition in different communities . Thyroid nodules are mostly benign . Almost thyroid cancers (TCs) are found as nodules. In the USA, TC accounts for about 1% of all new malignancies, but the annual incidence is reported to be increasing .
Risk factors associated with the development of TCs include a history of irradiation, a family history of medullary TC, and age less than 20 or more than 60 years . Also the risk of development of malignancy is increased in solitary more than in multiple nodularity [6,7].
Fine-needle aspiration cytology (FNAC) has been proven to be an accurate method for differentiating benign from malignant thyroid nodules [8,9]. In some series, FNAC results were nondiagnostic in 20-25% of the patients, with false-positive and false-negative results up to 5% .
Thyroid-stimulating hormone (TSH) is the main regulator of thyroid cell differentiation and growth; this action of TSH is also retained in malignant cells of differentiated thyroid cancers (DTCs) . There is an increased risk of thyroid malignancy with increased serum TSH concentrations in patients with nodular thyroid diseases (NTDs)[12-15]. Also, the stage of thyroid malignancy may be worse with higher TSH levels [16-18]. It is not clear whether TSH is involved in the pathogenesis of thyroid malignancy, or in the progression of established malignancy, or both .
Treatment of DTCs depends on total thyroidectomy (with cervical lymphadenectomy if lymph nodes were affected), radioactive iodine therapy for ablation of active thyroid remnants or metastases, and suppressive treatment with l-thyroxine . A high dose of l-thyroxine to suppress the secretion of TSH (to maintain TSH level lower than 0.1 mIU/l) is associated with a lower recurrence rate and cancer-related death, and higher overall survival .
There is increasing evidence that the serum concentration of TSH is an independent predictor for the diagnosis of thyroid malignancy in patients with NTD. Furthermore, preoperative serum TSH concentrations are higher in patients with more aggressive tumors, suggesting a potential role for TSH in the progression of DTC. On the basis of these observations, patients with higher serum TSH concentrations and borderline cytological results of FNAC may require more aggressive investigation and treatment when compared with those with lower baseline TSH levels. The aim of the present study was to evaluate the relationship between elevated TSH and DTC in a sample of Egyptian patients with NTD.
| Materials and methods|| |
This was a prospective, interventional study carried out at the Department of Surgery, Al-Azhar University Hospitals, in the period between September 2010 and March 2013. It was carried out on 100 patients (79 women and 21 men), with a mean age of 46.0 ± 12.7 years. They presented with NTD [75 patients had multinodular goiter (MNG) and 25 had a solitary thyroid nodule].
Egyptian patients between 20 and 68 years of age with NTD (MNG or a solitary thyroid nodule) were included in the study.
Patients with recurrent goiter, a history of malignancy in the head and neck, a history of irradiation to the neck, and patients declared unfit for general anesthesia or surgery because of other comorbid factors were excluded from the study.
All patients referred from outpatient clinics were admitted to the surgical department. The study was approved by the local ethics committee of the surgery department. All patients were interviewed using a standardized questionnaire and underwent a physical examination. The questionnaire inquired about the history in terms of onset, course, duration, previous malignancy, irradiation or surgery, and history of toxic, compression, or malignant manifestations.
A complete physical examination (general and local) was performed for all patients. Routine preoperative investigations including complete laboratory tests, ECG, chest radiograph, preoperative serum calcium concentration (total and ionized), and laryngoscopic examination of the vocal cords were performed for all patients.
Ultrasound examination of the neck confirmed NTD in all patients. FNAC was performed for patients with solitary thyroid nodules (25 patients) and thyroid scanning was also performed in these 25 patients.
The TSH concentration was evaluated preoperatively and grouped into the following three ranges: Less than 0.5 mIU/l, 0.5-5 mIU/l (euthyroidism), and higher than 5 mIU/l according to the method of Haymart et al. .
Thyroidectomy was planned for all cases. Patients were completely counseled on the procedure, outcome, and possible complications. A written consent was obtained.
Patients were admitted a day before surgery. Assessment for general anesthesia was performed. Preoperative preparations such as showering, sedation, and fasting 8 h before surgery were performed. An intravenous antibiotic (third-generation cephalosporin) was administered at the induction of anesthesia as prophylaxis. The operations were carried out under general anesthesia. The patients were placed on the operating table in the supine position with the neck extended and a pillow between the shoulders. Eighty-six patients underwent total thyroidectomy, whereas 14 patients underwent near-total thyroidectomy. During surgery, the procedure followed was meticulous and precise . It was ensured that all the recommended precautions were taken (careful dissection, adequate hemostasis, and recurrent laryngeal nerves were identified routinely on both sides and every attempt was made to identify and preserve the parathyroid glands). Suction drain was inserted routinely in all cases.
Postoperatively, all thyroid specimens were sent for histopathological examination. Effective analgesia was ensured and all patients were subjected to close observations for early complications (e.g. wound hematoma, suffocation). After their discharge from hospital, patients were followed up on a weekly basis for 4 weeks. At follow-up, patients were interviewed using the same standardized questionnaire as before, which included additional items related to surgery complications and results of histopathology.
| Results|| |
A total of 100 patients were included in the present study. They were between 20 and 68 years of age with a mean age of 46.7 ± 12.7 years. The most common age group in this study ranged from 35 to 55 years, 66 patients (66%). Of these 100 patients, 21 (21%) were men and 79 (79%) were women, with a male to female ratio of approximately 1 : 4. The median duration of symptoms was 2.2 years. Compression manifestations were present in 74 patients (74%), 63 patients presented with neck swelling (63%), two patients showed change of voice (2%), two patients had referred pain to the ear (2%), and one patient had dysphagia (1%). Neck ultrasound confirmed NTD in all patients (100%), FNAC was performed in 25 patients (25%), and thyroid scanning was performed in 25 patients (25%). Total thyroidectomy was performed in 86 patients (86%), whereas near-total thyroidectomy was performed in 14 patients (14%) [Table 1]. The mean hospital stay for both procedures was 2 days.
Histopathological examination was performed for all cases; the final data showed no evidence of malignancy in 83 patients (83%) (benign group), whereas malignant lesions were present in 17 patients (17%) (malignant group).
In the benign group, 67 patients were women (80.7%) and 16 patients were men (19.3%). The mean age was 49.7 ± 12.1 years. Sixty-five patients had MNG (78.3%) and 18 patients had a solitary thyroid nodule (21.7%). The preoperative mean TSH level was 1.72 ± 1.4 mIU/l [Table 2].
The analysis of the results was carried out on the basis of the following:
Preoperative thyroid-stimulating hormone level: The preoperative mean TSH level in the benign group was 1.72 ± 1.4 mIU /l, whereas the mean TSH concentration in the malignant group was 2.61 ± 2.2 mIU/l. Thus, the TSH levels were higher in patients with a final diagnosis of DTC.
Patients with TSH level < 0.5mlU/L were 13; one of them only was malignant (7.6%), patients with TSH level 0.5-5mlU/L (euthyroidism) were 82; 14 of them were malignant (17%), while patients with TSH level >5mlU/L were 5; two of them were malignant (40%) [Figure 1].
|Figure 1: Incidence of benign and malignant goiters according to the level of thyroid-stimulating hormone.|
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Findings of histopathological examination: In the malignant group, 12 patients were women (70.5%) and five patients were men (29.5%). The mean age was 45.2 ± 13.2 years. There were 10 patients with MNG (58.8%) and seven patients with a solitary thyroid nodule (41.2%). Papillary thyroid carcinoma (PTC) was found in 15 patients (88.2%), whereas follicular TC was found in two patients (11.8%). The preoperative mean TSH level was 2.61 ± 2.2 mIU/l [Table 3].
| Discussion|| |
NTD is a risk factor for epidemiologically ascertained TC. TC was found in mice following a diet lacking in iodine; a reduction in the mortality rate for TC registered in Switzerland following supplementation of iodine in table salt has confirmed this. Studies have shown that patients with NTD have a higher incidence of carcinoma than the general population .
In published reports, the incidence of carcinoma in MNG is reported at a percentage that varies from 7 to 17% . Furthermore, it seems that there is no statistically significant difference between the incidence of TC in patients with a solitary nodule as shown in the postoperative histopathologic examination and those with MNG . Thus, multinodularity does not seem to be a certain indicative factor of benign disease .
The present study found DTC in 17 patients out of 100 (17%) treated with thyroidectomy for NTD, which is in agreement with similar studies in the literature, with an increase in the incidence of DTC in patients with a solitary thyroid nodule (seven patients out of 25, 28%) than in patients with MNG (10 patients out of 75, 13.33%).
During the last few years, a number of studies have confirmed that the incidence of DTCs has increased worldwide [25,26]. In 2006, Boelaert et al. , in their study on 1500 patients, found that the incidence of TCs increases with higher TSH levels. These results were also confirmed by Polyzos et al.  in their study on 565 patients who had palpable thyroid nodules.
Haymart et al.  in a series of 843 patients subjected to thyroid surgery, reported a frequency of DTC of 16% when TSH was less than 0.06 mIU/l and 52% when TSH was higher than 5.00 mIU/l.
The relationship between serum TSH levels and the risk of PTC was analyzed by Fiore et al.  in 10 178 patients with a clinical diagnosis of nodular goiter and with a cytological diagnosis of PTC (n = 497) and benign NTD (n = 9681). Serum TSH was significantly higher in PTC (median, 1.10 mIU/l) than in patients with benign NTD (median, 0.70 mIU/l), whereas serum concentrations of both free T3 and free T4 were not significantly different. The frequency of PTC was directly related to serum TSH, being the lowest in patients with subnormal TSH values (51 of 2024; 2.5%) and the highest in patients with TSH values between 1.6 and 3.4 mIU/l (152 of 1665; 9.1%).
Gul et al. , in a series of 441 patients, reported that serum T3 and T4 were lower, whereas serum TSH was higher in the patients with TC compared with patients with benign thyroid lesions. The same result was obtained by Hands et al.  in a series of 269 patients. Fiore et al.  suggested that the probability of PTC increases about 11% for each 1 mIU/l increase in TSH above the normal value.
Zafon et al.  reported that the TSH concentration was significantly higher in patients with DTC (2.08-2.1 mIU/l) than in benign thyroid disease (1.36-1.62 mIU/l). Moreover, he subdivided the malignant group into patients with papillary thyroid microcarcinomas and TC of larger size; he found a direct relationship between increase in tumor size and increase in the TSH level. Fiore et al.  and Haymart et al.  found that there was also a relation between a higher TSH concentration and advanced stage of malignancy, not only the risk to develop malignancy.
In the present study, the preoperative TSH level for the malignant patients showed that one patient (out of 13) had a TSH level less than 0.5 mIU/l (7.6%), 14 patients (out of 82) had a TSH level 0.5-5 mIU/l (17%), and two patients (out of five) had a TSH level higher than 5 mIU/l (40%). These figures are comparable with similar studies in the literature.
Gandolfi et al.  reported that in 13.7% of the patients operated for MNG, during the definitive histopathological examination, a pattern of MNG associated with carcinoma was observed. The histopathological type of carcinoma associated more frequently with MNG was shown to be the papillary (62.5%). Follicular carcinoma was found in 37.5%.
In the present study, 17 out of 100 patients (17%) operated for NTD were found, after histopathological examination, to harbor malignant lesions. PTC was found in 15 patients (88.2%), whereas follicular TC was found in two patients (11.8%).
| Conclusion|| |
There is a relation between the serum TSH and development of DTCs in NTD as the risk of thyroid malignancy increases with high serum TSH concentrations and, even within normal ranges (0.5-5 mIU/l), higher TSH values are associated with a higher frequency and more advanced stage of TC.
| Acknowledgements|| |
| References|| |
|1.||Hegedus L. The thyroid nodule: clinical practice. N Engl J Med 2004; 351:1764-1771. |
|2.||Knudsen N, Laurberg P, Perrild H. Risk factors for goiter and thyroid nodules. Thyroid 2002; 12:879-888. |
|3.||Ain K, Rosenthal S. In: Ain K, Rosenthal S, editors. Thyroid nodule. The complete thyroid book. New York, Chicago, London: McGraw-Hill; 2005; p. 115. |
|4.||Yu GP, Li JC, Branovan D. Thyroid cancer incidence and survival in the National Cancer Institute surveillance, epidemiology, and end results race/ethnicity groups. Thyroid 2010; 20:465-473. |
|5.||Inger PA. In: Braverman LE, editor. Evaluation and management of the euthyroid nodular and diffuse goiter. Diseases of the Thyroid. 2nd ed. Totowa: Humana Press; p. 217. |
|6.||Rago T, Fiore E, Scutari M. Male sex, single nodularity, and young age are associated with the risk of finding a papillary thyroid cancer on fine-needle aspiration cytology in a large series of patients with nodular thyroid disease. Eur J Endocrinol 2010; 162:763-770. |
|7.||Fiore E, Rago T, Provenzale MA. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: Thyroid autonomy may play a protective role. Endocr Relat Cancer 2009; 16:1251-1260. |
|8.||Castro MR, Gharib H. Thyroid fine-needle aspiration biopsy: progress, practice, and pitfalls. Endocr Pract 2003; 9:128-136. |
|9.||Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab 2012; 97:1134-1145. |
|10.||Chow LS, Gharib H, Goellner JR. Nondiagnostic thyroid fine-needle aspiration cytology: Management dilemmas. Thyroid 2001; 11:1147-1151. |
|11.||Garcia-Jimenez C, Santisteban P. TSH signalling and cancer. Arq Brasil Endocrinol Metabol 2007; 51:654-671. |
|12.||Boelaert K, Horacek J, Holder RL. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab 2006; 91:4295-4301. |
|13.||Haymart MR, Glinberg SL, Liu J. Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clin Endocrinol (Oxf) 2008; 71:434-439. |
|14.||Jonklaas J, Nsouli-Maktabi H, Soldin SJ. Endogenous thyrotropin and triiodothyronine concentrations in individuals with thyroid cancer. Thyroid 2008; 18:943-952. |
|15.||Jin J, Machekano R, McHenry CR. The utility of preoperative serum thyroid-stimulating hormone level for predicting malignant nodular thyroid disease. Am J Surg 2010; 199:294-297. |
|16.||Polyzos SA, Kita M, Efstathiadou Z. Serum thyrotropin concentration as a biochemical predictor of thyroid malignancy in patients presenting with thyroid nodules. J Cancer Res Clin Oncol 2008; 134:953-960. |
|17.||Haymart MR, Repplinger DJ, Leverson GE. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J Clin Endocrinol Metab 2008; 93:809-814. |
|18.||Gerschpacher M, Gobl C, Anderwald C. Thyrotropin serum concentrations in patients with papillary thyroid microcancers. Thyroid 2010; 20:389-392. |
|19.||Boelaert K. The association between serum TSH concentration and thyroid cancer. Endocr Relat Cancer 2009; 16:1065-1072. |
|20.||Cooper DS, Doherty GM, Haugen BR. Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer Thyroid 2009; 19:1167-1214. |
|21.||Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 2010; 20:135-146. |
|22.||Bron PL, O'Brien CJ. Total thyroidectomy for clinically benign disease of the thyroid gland. Br J Surg 2004; 91:569-574. |
|23.||Gandolfi PP, Frisina A, Raffa M, Renda F, Rocchetti O, Ruggeri C, Tombolini A. The incidence of thyroid carcinoma in multinodular goiter: retrospective analysis. Acta Bio Medica Ateno Parmense 2004; 75:114-117. |
|24.||Sachmechi I, Miller E, Varatharajah R. Thyroid carcinoma in single cold nodules and in cold nodules of multinodular goiters. Endocr Pract 2000; 6:110-112. |
|25.||Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. J Am Med Assoc 2006; 295:2164-2167. |
|26.||Leenhardt L, Grosclaude P, Chérié-Challine L. Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 2004; 14:1056-1060. |
|27.||Gul K, Ozdemir D, Dirikoc A. Are endogenously lower serum thyroid hormones new predictors for thyroid malignancy in addition to higher serum thyrotropin? Endocrine 2010; 37:253-260. |
|28.||Hands KE, Cervera A, Fowler LJ. Enlarged benign-appearing cervical lymph nodes by ultrasonography are associated with increased likelihood of cancer somewhere within the thyroid in patients undergoing thyroid nodule evaluation. Thyroid 2010; 20:857-862. |
|29.||Fiore E, Rago T, Latrofa F. Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with l-thyroxine. Endocr Relat Cancer 2011; 18:429-437. |
|30.||Zafon C, Obiols G, Baena JA. Preoperative thyrotropin serum concentrations gradually increase from benign thyroid nodules to papillary thyroid microcarcinomas, then to papillary thyroid cancers of larger size. J Thyroid Res 2012; 5:721. |
[Table 1], [Table 2], [Table 3]