|Year : 2016 | Volume
| Issue : 2 | Page : 261-264
Differentiated thyroid cancer in Iran – initial observations, histological features, management of the disease, and tumor recurrence: A review of 1689 cases
M Moslehi1, Z Shahi1, S Badihian2, P Jalalpour2, M Sedghian2, G Motamedi2, G Tavakol2
1 Department of Medical Physics and Biomedical Engineering, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Students' Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Web Publication||6-Jan-2017|
Students' Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Aim: The main objective of this study was to define some histopathological aspects of differentiated thyroid cancer (DTC), describe the disease management, and evaluate potential predicting factors for tumor recurrence in Iran. Materials and Methods: Medical records of 1689 patients of DTC treated over a 15-year period at a referral hospital located in the central region of Iran were reviewed retrospectively. Results: The female/male ratio was 3.78. The mean size of tumors was 23.35 mm. Most patients had papillary thyroid cancer (PTC) followed by follicular thyroid cancer (FTC) (83% and 5.5%, respectively). Lymph node involvement was seen in 27.6% of patients, and 3.6% of them had distant metastasis. Tumor recurrence was reported in 36.4% of patients. Higher stages of cancer, presence of lymph node involvement, presence of distant metastasis, larger tumor size, history of goiter, and higher doses of 131-Iodine at the first admission were associated with more chance of recurrence (P < 0.05). Comparing features of PTC and FTC, we found a more invasive behavior in FTC patients, including more capsular and near tissue invasion, higher stages of cancer, more frequent distant metastasis, and larger tumor size. Conclusion: This study provides useful information on characteristics of DTC, its management, and some prognostic factors. Our findings suggest that higher stages of cancer at diagnosis, presence of lymph node involvement, presence of distant metastasis, larger tumor size, history of goiter, and higher doses of 131-iodine administered at the first admission are associated with more chance of tumor recurrence. Furthermore, we found that FTC follows a more aggressive behavior and recommends clinicians to handle FTC patients more cautiously.
Keywords: Differentiated thyroid cancer, histology, predicting factors, radioiodine, thyroidectomy, tumor recurrence
|How to cite this article:|
Moslehi M, Shahi Z, Badihian S, Jalalpour P, Sedghian M, Motamedi G, Tavakol G. Differentiated thyroid cancer in Iran – initial observations, histological features, management of the disease, and tumor recurrence: A review of 1689 cases. Indian J Cancer 2016;53:261-4
|How to cite this URL:|
Moslehi M, Shahi Z, Badihian S, Jalalpour P, Sedghian M, Motamedi G, Tavakol G. Differentiated thyroid cancer in Iran – initial observations, histological features, management of the disease, and tumor recurrence: A review of 1689 cases. Indian J Cancer [serial online] 2016 [cited 2019 Aug 21];53:261-4. Available from: http://www.indianjcancer.com/text.asp?2016/53/2/261/197727
| » Introduction|| |
Thyroid cancer is the most frequent endocrine malignancy,, standing as the 12th cancer in male and 9th cancer in female in Iran. Studies have reported an increasing incidence of thyroid cancer in the world in recent years.,,, Differentiated thyroid cancer (DTC) is a slowly growing disease that accounts for a vast majority of thyroid cancers  and has an incidence rate of 0.5–10/10,000 population. The prognosis is good and it leads to death in 0.3% of cases.,, DTC is made up of two major subsets: Papillary thyroid cancer (PTC) which comprises about 85% of all cases and follicular thyroid cancer (FTC) which consists about 10% of all cases.,
Management of DTC is primary thyroidectomy, followed by choices of radioiodine treatment and/or external beam radiotherapy.,,, DTC characteristically takes up radioactive iodine (RAI), which may be used as a tool for treating distant metastases and local tumors., RAI ablation after total or near total thyroidectomy (NTT) is the standard procedure in patients with DTC with the exception in patients with unifocal PTC ≤1 cm in diameter who lack evidence of metastases, thyroid capsule invasion, history of radiation exposure, and unfavorable histology., The dose routinely used for ablation varies greatly worldwide. The usual dose is 80–150 mCi, depending on distant metastases.,
In contrast to more common malignancies, DTC is distinguished for its slow clinical course and potential for late relapses. Various factors associated with recurrence have been suggested in previous studies, including age, gender, extrathyroidal tumor extension, tumor size, histology, extent of lymph node metastases, and presence of distant metastases at the time of diagnosis.,
Considering the increasing rate of thyroid cancer in the world, we need to clarify the risk and prognostic factors of thyroid cancer. In this study, we analyzed histological and clinical characteristics of DTC, its management, tumor recurrence, and its potential predicting factors in a large group of patients in the central region of Iran.
| » Materials and Methods|| |
Our study is a cross-sectional population-based study carried out at Seyed Al-Shohada Medical Center, a referral hospital for diagnosis and treatment of cancer located in the city of Isfahan, in the central region of Iran, and affiliated to Isfahan University of medical sciences. A total of 1689 patients with a diagnosis of DTC and history of thyroidectomy were investigated from 1999 to 2014, over a 15-year period. The diagnosis was based on clinical assessment and fine-needle aspiration cytology and it was confirmed by histopathological reports from the Department of Pathology.
Medical records of all patients were reviewed for age, sex, histopathological report, cancer staging, number of hospitalizations, tumor recurrence, type of surgery performed, RAI management dosage, history of Hashimoto thyroiditis (HT), and history of goiter. The operative procedures were bilateral in the form of TT (with or without central compartment lymph node resection) or NTT, selected by the general surgeon according to patient status, and all patients referred to our center were considered for RAI ablation 4–6 weeks after surgical treatment. Multiple admissions in the same patient were counted as one case. The tumor node metastasis staging system was used based on the American Joint Committee on Cancer/Union for International Cancer Control classification system to describe tumor size and spread. The study was approved by the regional bioethics committee of Isfahan University of Medical Sciences.
Statistical analysis was carried out employing independent simple t-test, Chi-square test, and Cox proportional hazard analysis, using SPSS 18 (Chicago, IL). P < 0.05 was considered statistically significant.
| » Results|| |
A total of 1689 patients were enrolled in the study, of those 20.8% were male, with a mean age of 41.98 ± 15.28 years (44.47 ± 16.21 years in male and 40.1 ± 14.9 in female patients). The history of goiter and HT was present in 18.2% and 9.5% of patients, respectively.
The frequencies of tumor types were as follows: 83% papillary, 5.5% follicular, 1.3% medullary, and 0.7% for other tumor types, and the mean size of tumors was 23.35 ± 14.21 mm. Capsular invasion was reported in 9.2% of patients, near tissue invasion in 4.2% of patients, and multicentrity in 9.2% of them. Most patients had stage 1 thyroid cancer (67.5%), and stage 2, 3, and 4 were reported in 10.6%, 5.8%, and 4% of cases, respectively. Lymph node involvement was reported in 26.7% of cases with the superiority of cervical lymph node involvement (317 cases of cervical, 43 cases of supraclavicular, 45 cases of substernal, and 44 cases of other sites involvement). Metastasis was present in 3.6% of patients, including lung and neck as the most common sites followed by liver (1.4%, 1.3%, and 0.7%, respectively).
We compared patients' characteristics, history, and tumor features between cases of papillary and follicular cancer. Capsular invasion was found to be significantly more frequent in patients with FTC compared to patients with PTC (29.8% vs. 8.9%, respectively; P < 0.005), as well as near tissue invasion (11.4% vs. 4.3% respectively; P < 0.005). FTC tended to present with higher stages of cancer in patients compared to PTC (P < 0.05). In PTC patients, we observed stage 1–4 in 78.2%, 11.6%, 6.2%, and 4% of patients, respectively, while these stages were seen in 57.2%, 17.9%, 11.9%, and 13% of FTC patients. Furthermore, patients with FTC experienced all kinds of metastasis more frequently compared to PTC patients (13.2% compared to 0.8% all cases of metastases, respectively; P < 0.05). In comparison with PTC patients, those with FTC were older (40.05 ± 14.91 vs. 47.53 ± 17.07; P < 0.005) and had larger tumor sizes (30.84 ± 17.90 vs. 22.82 ± 13.52; P < 0.005). The 131-Iodine dosage administered in the first admission (133.45 ± 35.08 vs. 152.17 ± 40.54) was significantly higher in FTC patients (P < 0.005). Cox proportional hazard analysis showed that none of the mentioned factors are significantly different among groups with and without tumor recurrence.
TT was performed in 53.6% of patients, followed by NTT and TT with central compartment lymph node resection (9.7% and 1.6% of patients, respectively). The mean dosage of 131-Iodine prescribed in the first admission was 134.84 ± 36.18 mCi (range: 100–300; median: 125 mCi). Administered dosage of 131-Iodine was 100 mCi in 37.1% of cases, followed by 150 mCi in 27.6% and 125 mCi in 16.8% of cases.
Among all patients, 34.6% experienced tumor recurrence, including 20.1% with single recurrence, 8.3% with double recurrences, and 12.7% with three or more recurrences. We found that higher stages of cancer are associated with higher chance of tumor recurrence as we observed 33.2% of recurrences in patients with stage 1 cancer, 43.8% in stage 2, 47.4% in stage 3, and 49.2% in stage 4 (P < 0.05). Furthermore, patients with cervical, supraclavicular, substernal, and other lymph node involvements experienced 48.7%, 41.8%, 62.2%, and 44.1% of tumor recurrences, respectively, while 29.9% of cases without lymph node involvement experienced tumor recurrence (P < 0.05). Moreover, 68.4% of patients with distant metastases showed tumor recurrence, while those without metastases had tumor recurrence in 33.7% of cases (P < 0.05). Positive history of goiter was seen to be associated with lower tumor recurrence (29.7% compared to 36.2%, respectively; P < 0.05). Larger tumor size was reported in patients with tumor recurrence (24.93 ± 15.41 compared to 22.55 ± 13.47; P < 0.05) as well as higher doses of 131-Iodine on admission (148.60 ± 40.33 compared to 127.33 ± 31.26 respectively; P < 0.05). Cox proportional hazard analysis showed that none of the mentioned factors are significantly different among groups with and without tumor recurrence. Please note that missing cases are also calculated for all the presented findings but are not mentioned in the text.
| » Discussion|| |
The present study was an introductory investigation in the central region of Iran regarding DTC histological and clinical features, surgery type, radioiodine therapy, tumor recurrence and its predicting factors, cancer staging, patients' characteristics, and past medical history of goiter and HT. To the best of our knowledge, this is the first study in Iran reporting the mentioned items.
In our report, demographic data showed a female-to-male ratio of 3.78 which is consistent with female predominance reported in the previous studies., The mean age of patients was 41.98 ± 15.28, which shows that the majority of patients are in the middle ages. The previous reports have shown the same age pattern as well. PTC was the most common tumor with a frequency of 83%, followed by FTC with 5.5% and other types for 2%. PTC is known as the most common tumor type among DTCs and its predominance was seen in all previous studies.,
Epidemiologically, risk factors of thyroid cancer are irradiation, the presence of thyroid adenoma and multinodular goiter., The association of HT and PTC has been suggested a long time ago. The causal association of the two diseases remains controversial, with various authors reporting no association between HT and PTC and others describe a variable frequency as high as 38%.,, A study in Iran provided data against the suggested cause-and-effect relation between goiter and thyroid cancer. We found a history of goiter and HT in 18.2% and 9.5% of our patients, respectively; however, we did not have any healthy control group to compare these rates with them.
We observed that patients with diagnosis of FTC are significantly older than patients with PTC. This finding is also reported in the previous studies. Comparing tumor features between patients with PTC and FTC, we found more frequency of capsular invasion and near tissue invasion in patients with FTC. Regarding cancer stage at the time of diagnosis, these patients were also diagnosed in higher stages of cancer and more rates of metastasis. Larger tumor sizes were also seen in the group of patients with FTC. FTC is reported to have a more aggressive behavior compared to PTC in the previous studies., Machens et al. reported larger tumor sizes among patients with FTC as well as more rates of distant metastasis. Therefore, our results are consistent with the previous reports comparing PTC and FTC.,, Lymph node involvement was seen to be almost similar among patients with PTC and FTC, with higher but not significant rates in PTC patients. The previous studies have reported significantly more frequent lymph node metastasis among PTC patients. Regarding our other results and previous findings, we believe that it may be due to incomplete medical records of these patients.
Metastasis was seen in 3.6% of our cases, which is lower than the amount reported in similar studies in Iran. Studies from other countries have also reported a higher frequency of metastasis in patients diagnosed with DTC., This difference can be explained by incomplete medical evaluation of referred patients to our hospital. The long-term period in which cases were entered in this study, less advanced diagnostic tools, and less common use of those tools used for the evaluation of distant metastasis may be another explanation for the observed difference as well.
In our series, 34.6% of patients experienced tumor recurrence. The previous studies have reported the recurrence rate of 7.7% to 9.8%, however, recurrence rates more than 25% are also reported in patients with aggressive DTC. We found that higher stages of cancer are associated with more chance of recurrence, which was expected. Furthermore, we observed more chance of recurrence in patients with lymph node involvements and distant metastasis. Tumor size was increased in patients who experienced tumor recurrence as well. We found no difference in recurrence rate between PTC and FTC. Distant metastasis is reported to be highly associated with tumor recurrence in almost all previous studies., Steinmüller et al. also reported larger tumor size as a factor associated with more relapses of the tumor, especially in patients with PTC. Some other studies also suggest larger sizes of tumor and FTC are more likely to recur in future although some other studies report no correlation between them.,, In this study, we found that positive history of goiter is associated with more chance of tumor recurrence. As discussed before, the role of goiter in developing DTC has been suggested previously;, however, none of the previous studies have evaluated the history of goiter as a prognostic factor.
TT and radioiodine are also suggested to decrease chances of tumor recurrence, while we found increased tumor relapse in patients who underwent TT with central compartment lymph node resection. Considering the small number of our patients who underwent TT with central compartment lymph node resection and the notable number of missing data on surgical approach, it seems that our results cannot be generalized to all DTC cases. Patients' age and sex are also reported as prognostic factors in some previous studies; however, these findings are still controversial.,, We found no significant difference in these factors among groups of patients with and without tumor recurrence.
TT was performed in 53.6% of cases, and the rest underwent NTT (9.7%) and TT with central compartment lymph node resection (1.6%). We had missing data on surgical approach in 34.9% of our cases. These patients were operated by various surgeons during 15 years. Therefore, our data on surgical intervention may not be consistent with latest recommendations for these patients. Thyroidectomy with the administration of RAI and/or external beam radiation is considered the standard care for DTC currently., Based on recent guidelines of the American Thyroid Association, total or NTT is suggested as the main surgical approach for all patients with tumor size >4 cm, or those with gross extrathyroidal extension, apparent lymph node metastasis, or distant metastasis, and as the alternative surgical approach for patients with tumor size <4 cm and >1 cm.
RAI was administered for patients with the median dosage of 125 mCi (ranging from 100 to 300 mCi). The administered dosage is more than the amount administered in the USA, while it is analogous to the dosage reported in some European or Asian studies., It is recommended that 100 mCi of RAI would improve patients' quality of life significantly.,, Based on our results, patients who were treated with higher dosages of RAI were expected to have more relapses. Although it may appear that higher dosages of RAI may be protective of further relapses, some studies have suggested that it cannot be considered as a deterrent factor for tumor recurrence yet., Another explanation for this finding is that patients who are at higher stages of cancer at the time of diagnosis may be treated with higher dosages of RAI and also will experience more relapses in future.
Our study had some limitations that must be addressed. First, the cross-sectional design of our study was followed by difficulty to make causal inference, presence of missing data, and underestimation of some variables. Second, we had notable missing data on surgical approach. Third, medical evaluation was incomplete in some referred patients. Fourth, we did not follow patients to evaluate the survival rate and prognostic factors associated with survival.
| » Conclusion|| |
Our results suggest that higher stages of cancer at diagnosis, presence of lymph node involvement, presence of distant metastasis, larger tumor size, history of goiter, and higher doses of 131-Iodine administered at the first admission are associated with more chance of tumor recurrence. Furthermore, we observed more invasive behavior from FTC compared to PTC which suggests that FTC needs to be evaluated, managed, and followed more cautiously. Further studies are recommended to compare management of DTC subtypes and evaluate the disease prognostic factors more precisely. Furthermore, more epidemiologic studies are recommended in Iran and Middle Eastern countries to assess demographic data and histopathological characteristics of the disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Gomez Segovia I, Gallowitsch HJ, Kresnik E, Kumnig G, Igerc I, Matschnig S, et al.
Descriptive epidemiology of thyroid carcinoma in Carinthia, Austria: 1984-2001. Histopathologic features and tumor classification of 734 cases under elevated general iodination of table salt since 1990: Population-based age-stratified analysis on thyroid carcinoma incidence. Thyroid 2004;14:277-86.
Gandolfi PP, Frisina A, Raffa M, Renda F, Rocchetti O, Ruggeri C, et al.
The incidence of thyroid carcinoma in multinodular goiter: Retrospective analysis. Acta Biomed 2004;75:114-7.
Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Malekezadeh R, Parkin DM. Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev 2005;6:359-63.
Li N, Du XL, Reitzel LR, Xu L, Sturgis EM. Impact of enhanced detection on the increase in thyroid cancer incidence in the United States: Review of incidence trends by socioeconomic status within the surveillance, epidemiology, and end results registry, 1980-2008. Thyroid 2013;23:103-10.
Morris LG, Sikora AG, Tosteson TD, Davies L. The increasing incidence of thyroid cancer: The influence of access to care. Thyroid 2013;23:885-91.
Enyioha C, Roman SA, Sosa JA. Central lymph node dissection in patients with papillary thyroid cancer: A population level analysis of 14,257 cases. Am J Surg 2013;205:655-61.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al.
2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al.
Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214.
Chow SM, Law SC, Au SK, Leung TW, Chan PT, Mendenhall WM, et al.
Differentiated thyroid carcinoma: Comparison between papillary and follicular carcinoma in a single institute. Head Neck 2002;24:670-7.
Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, et al.
International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control 2009;20:525-31.
Larson SD, Jackson LN, Riall TS, Uchida T, Thomas RP, Qiu S, et al.
Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway. J Am Coll Surg 2007;204:764-73.
Sherman SI, Brierley JD, Sperling M, Ain KB, Bigos ST, Cooper DS, et al.
Prospective multicenter study of thyroiscarcinoma treatment: Initial analysis of staging and outcome. National Thyroid Cancer Treatment Cooperative Study Registry Group. Cancer 1998;83:1012-21.
Iftikhar A, Naseeb AK, Khwaja A, Mati H, Karim K, Hameeda N. Patterns of differentiated thyroid cancer in Baluchistan Province of Pakistan: Some initial observations. Med J Malaysia 2011;66:322-5.
Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P, Oyen WJ, et al.
Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 2008;35:1941-59.
Clarke SE. Thyroid disease. In: Clinical Nuclear Medicine. Boston, MA: Springer; 1998. p. 9-25.
Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: A population-based, nested case-control study. Cancer 2006;106:524-31.
Larijani B, Aghakhani S, Khajeh-Dini H, Baradar-Jalili R. Clinico-pathological features of thyroid cancer as observed in five referral hospitals in Iran – A review of 1177 cases. Acta Oncol 2003;42:334-7.
Al-Salamah SM, Khalid K, Bismar HA. Incidence of differentiated cancer in nodular goiter. Saudi Med J 2002;23:947-52.
Dvorkin S, Robenshtok E, Hirsch D, Strenov Y, Shimon I, Benbassat CA. Differentiated thyroid cancer is associated with less aggressive disease and better outcome in patients with coexisting Hashimotos thyroiditis. J Clin Endocrinol Metab 2013;98:2409-14.
Liu CL, Cheng SP, Lin HW, Lai YL. Risk of thyroid cancer in patients with thyroiditis: A population-based cohort study. Ann Surg Oncol 2014;21:843-9.
Machens A, Holzhausen HJ, Dralle H. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer 2005;103:2269-73.
Wartofsky L. Increasing world incidence of thyroid cancer: Increased detection or higher radiation exposure? Hormones (Athens) 2010;9:103-8.
Passler C, Scheuba C, Prager G, Kaczirek K, Kaserer K, Zettinig G, et al.
Prognostic factors of papillary and follicular thyroid cancer: Differences in an iodine-replete endemic goiter region. Endocr Relat Cancer 2004;11:131-9.
Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Prognostic factors in papillary and follicular thyroid carcinoma: Their implications for cancer staging. Ann Surg Oncol 2007;14:730-8.
Mallick U, Sipos JA, Mazzaferri EL. Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol) 2010;22:395-404.
Shaha AR. Recurrent differentiated thyroid cancer. Endocr Pract 2012;18:600-3.
Steinmüller T, Klupp J, Rayes N, Ulrich F, Jonas S, Gräf KJ, et al.
Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg 2000;166:29-33.
Frasoldati A, Pesenti M, Gallo M, Caroggio A, Salvo D, Valcavi R. Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma. Cancer 2003;97:90-6.
Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998;82:375-88.
Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418-28.