Kovalenko and Tarashchenko: Post-Chornobyl Papillary Thyroid Carcinoma



Problem statement and analysis of the recent research

The problem of timely diagnosis and radical treatment of papillary thyroid carcinomas remains relevant for the population of Ukraine, despite 30 years elapsed after the Chornobyl accident. Long-term follow-up of the cohort of persons affected by radiation has shown a persistent risk of papillary thyroid cancer [7, 8]. In 2015, the incidence of malignant thyroid tumor reached 6.9 cases per 100,000 population in Ukraine [1]. In 2015, 38,526 patients with thyroid carcinoma were registered and treated in Ukraine. Early ultrasound and cytological diagnosis has significantly improved, making it possible to diagnose tumors at the early stages of the development. According to statistical reports in 2015, 30,613 new thyroid neoplasias were diagnosed in Ukraine. Among them 2,955 were malignant (9.6%). High surgical activity is maintained in treatment of thyroid diseases. In 2015, 8,486 interventions on the thyroid gland (2.98 surgeries per 10,000 population) were performed in Ukraine. The proportion of surgeries performed for oncologic indications has considerably increased. The key issues in treatment of thyroid carcinomas remain the accuracy of the preoperative cytomorphological diagnosis, risk stratification and treatment aggressiveness.

The objective of the research was to evaluate the results of treatment as well as to determine an optimal protocol of diagnosis, therapy and monitoring of patients with thyroid papillary carcinoma developed among the population of Ukraine in the period after the Chornobyl disaster.

Materials and methods

The results of treatment of patients with histologically proven papillary thyroid cancer, who were on the territory of Ukraine in 1986, are presented. Computer database included 6,239 patients with papillary thyroid carcinoma. All patients underwent radical treatment during 1990-2015. Follow-up period lasted from 1 to 25 years after initial surgery, on average 11.8±2.1 years. The age of patients ranged from 7 to 74 years. The mean age was 38.3±7.4 years. There were 5,003 (80.2%) females and 1,236 (19.8%) males (F: M ratio=4.0:1.0). We evaluated clinical manifestations of the disease and the nature of treatment. The analysis of treatment results was made based on the data on the number of relapses, which developed after the initial surgical operation, and the number of deaths due to thyroid cancer.

Results and Discussion

The first cases of papillary thyroid carcinomas were noted four years after the Chornobyl accident in children living in radiation-contaminated areas of Ukraine. The incidence increased mainly due to patients exposed to ionizing radiation at the age of 0 - 4 years [2, 3, 7]. Since 1989, there was an increase in the incidence of papillary thyroid cancer among children from affected regions of Ukraine from 0.4 - 0.6 cases per million children during the period before the accident to 4 cases per million children during 1992-1994.

60% of cases were detected in five northern regions (Kyiv, Chernihiv, Zhytomyr, Cherkasy, and Rivne) which were the most heavily contaminated with radioactive iodine areas. The incidence reached 11.5 cases per million children [2, 3, 7, 8].

Papillary thyroid carcinomas developed in the affected population of Ukraine in the early post-Chornobyl period (1990-1997) were characterized by an aggressive course. In half of patients (51.7%) extrathyroidal spread of tumor (the T3 and T4 categories) was observed. In almost all cases, in children there were found not microcarcinomas but clinically significant tumors. Local spread of the tumor beyond the limits of the thyroid gland in some cases led to the disturbances in the respiratory tract, esophagus, major vessels, and nerves. Patients complained of difficulty in swallowing (0.9%), respiratory difficulty (0.6%), hoarseness (3.2%) and pain in the neck (0.3%). T2 category tumors were noted in 185 (29.4%) patients. T1 category tumors being prognostically more favorable were observed in 119 (18.9%) cases. 231 (36.7%) patients were diagnosed with regional metastases to cervical lymph nodes. 33 (5.2%) patients developed distant metastases to the lungs.

Morphological examination of tumors showed that more than 90% of cases represented papillary carcinoma. Typical papillary carcinomas in children and adolescents were observed only in a small number of cases. The most common papillary carcinomas had a solid, follicular or mixed solid-follicular structure. Similar carcinomas are combined in a single solid-follicular variant that is characterized by a wide intra-glandular spread, extension beyond the glandular capsule, lymphatic and vascular invasion, frequent metastases to cervical lymph nodes.

The preoperative diagnostic program was based on the determination of all thyroid focal lesions being cancerous. The objectification of the data of the initial examination was carried out by ultrasound investigation of the thyroid gland and cervical lymph nodes. We used high-frequency transducers (7.5-10 MHz) with mandatory thyroid scan in several planes and Doppler sonography of intrathyroidal blood flow. The ultrasound resolution was 2-3 mm, which allowed detecting carcinomas in the earliest stages of the development.

The decisive moment in confirming the diagnosis of thyroid carcinoma was performance of fine-needle aspiration biopsy of focal lesions in combination with cytology of tumor bioptate; the sensitivity of cytology in case of papillary thyroid carcinoma was 97.3%; the specificity was 88.5%; diagnostic accuracy was 97.7%.

The main controversial issue is the need for biopsy of the thyroid nodules of small size (less than 10 mm in diameter) being frequently detected in patients. In these cases, sonographic features being characteristic for malignancy were taken into account: the presence of microcalcifications, hypoechogenicity of nodule, its irregular shape and contours, the presence of solid component, chaotic intranodular hypervascularization. Sonographic characteristics of nodules and clinical pattern allow evaluating the risk of malignancy as well as help in making decision concerning biopsy performance. In the presence of indirect sonographic signs of malignancy and certain experience of the diagnostician, it was possible to obtain a sufficient for interpretation amount of cytologic material from carcinoma of the minimum size (up to 5-6 mm in diameter).

The issue of the method of treatment and choice of surgical volume in case of papillary thyroid carcinoma has been a subject of debate for many years [4, 5, 6, 9]. Today, there is no doubt that the method of choice in treatment of papillary thyroid carcinomas is extrafascial thyroidectomy. Thyroidectomy allows performing subsequent therapy with radioactive iodine as well as achieving better results of treatment and reducing the risk of relapse development compared to organ-saving surgery. Total thyroidectomy in papillary thyroid carcinoma was performed in the majority of patients: 5,278 (84.6%).

The most difficult problem for the surgeon is the choice of surgical volume in case of thyroid tumor of follicular structure (follicular neoplasm), when it is difficult to make cytomorphological diagnosis of malignancy before and during surgery. In such cases, extrafascial hemithyroidectomy should be considered as a minimum surgical volume. Such operations were used in 767 cases.

In case of organ-saving surgery and diagnosis of carcinoma during the final histological examination, there were discussed the indications for performing the “final thyroidectomy” as the second stage. Unfavorable histological variant of carcinoma, intrathyroid dissemination, tumor size greater than 10 mm, severity of capsular and vascular invasion, history of radiation exposure were considered as well. In our follow-up, 194 patients underwent the “final thyroidectomy”. In 961 (15.4%) patients, in the presence of minimally invasive encapsulated papillary carcinoma up to 1 cm, surgical volume (hemithyroidectomy) was recognized as a radical one.

The choice of surgical volume on neck lymphatic collectors in papillary thyroid carcinoma remains a debated issue. An important aspect of surgery is surgical revision of regional lymphatic collectors alongside with intraoperative express biopsy of the “sentinel” lymph nodes of the central compartment and omohyoid group of jugular basin on the affected side. In case of confirmed metastases, radical lymphadenectomy was performed according to anatomical landmarks of the neck. Neck dissection of different lengths was performed in 1,733 (27.8%) patients.

After radical surgery, all patients underwent ablation of residual thyroid tissue and radioiodine therapy of metastases, followed by suppressive therapy with thyroid medications. The monitoring of patients was carried out according to conventional protocols of the European Society for Medical Oncology (ESMO).

Over time, an improvement in the quality of ultrasound and cytological diagnosis allowed increasing the number of surgeries performed at the early stages of carcinoma development. During 1990-1997, the number of T1 category carcinomas of small size was observed in 119 (18.9%) cases, while during 1998-2005 their number increased to 463 (29.4%) cases, and during 2006-2015 it reached 2,416 (59.8%) cases. Naturally, this led to a decrease in the proportion of patients with common forms of T3 and T4 category carcinomas: 1990-1997=325 (51.7%) cases; 1998-2005=570 (36.2%) cases; 2006-2015=872 (21.6%) cases.

Despite the improvements in early diagnosis of papillary thyroid carcinomas, even small tumors in younger patients exhibited more aggressive biologic behavior. During 2010-2012, among 313 patients (age group under 18 years old at the time of the Chornobyl accident) with pT1 category papillary thyroid carcinoma, intrathyroid dissemination was detected in 26.8% of cases; regional metastases were diagnosed in 21.7% of patients.

It is noteworthy that the improvement of the diagnosis did not affect the incidence of recurrent and residual metastases, which began to become iodine-refractory. Repeated operations for metastases were performed in 8.3% of cases.

Since 2008, in our department thyroidectomy for papillary carcinoma has been supplemented with preventive dissection of the lymph collectors of the central compartment of the neck more frequently. These were cases of carcinomas confirmed by cytology without preoperative evidence of metastatic process according to ultrasound and macroscopic intraoperative visual evaluation.

It should be noted that performance of systematic central lymphodissection significantly increased the frequency of detecting metastases to level VI lymph nodes. Among 221 patients of “Chornobyl age”, during preventive central compartment lymph node dissection, the micrometastatic process was morphologically identified in 59.2% of cases. The use of anatomical surgical technique when removing the thyroid gland under visual monitoring of the recurrent laryngeal nerves and the parathyroid glands did not increase the rate of laryngeal and parathyroid complications (persistent laryngeal paresis in 2.1%, persistent hypoparathyroidism in 0.8%).

The long-term results of treatment were followed in 886 patients with papillary thyroid carcinoma, who were children or adolescents resided in radiation-contaminated regions of Ukraine in 1986. The obtained results confirmed that the method of choice in treatment of papillary thyroid cancer is thyroidectomy, supplemented, if indicated, with neck dissection followed by radioiodine ablation. In case of thyroidectomy there was a decrease in relapse proportion by 2.5 (3.8%) times compared to organ-saving surgery (9.7%).

The evaluation of the possibility of recurrence of papillary thyroid cancer depending on risk group did not reveal any significant differences. Even in the group of very low risk in case of minimally invasive papillary carcinoma, recurrent disease was detected in 2% of cases. In the group of low risk (as in the group of high risk) the proportion of relapses was 4.8%, which confirms the opinion that there is the need for performing total thyroidectomy in patients from radiation-contaminated regions of Ukraine even in case of minimally invasive papillary carcinomas.

The analysis of the causes of deaths showed that 6 (0.67%) persons died due to t papillary thyroid cancer. In 3 patients, the cause of death was acute cardiovascular insufficiency due to severe postoperative complications in case of tumors with extensive local invasion of the organs of the neck and the mediastinum, widespread regional and distant metastases. 3 patients died due to widespread metastases to the lungs being refractory to radioactive iodine therapy.

The effect of tumor extension in the thyroid gland (category T) and regional metastatic process (category N) on survival and mortality rates in papillary thyroid carcinomas was determined. The presence of extrathyroidal tumor invasion (the T4a and T4b categories) significantly reduced the relapse-free survival (from 96.1% to 93.0%) and increased cancer mortality (from 0.2% to 3.4%), without affecting the development of disease relapses. The risk of recurrence significantly increased due to the presence of metastases to cervical lymph nodes and the mediastinum (from 1.25% to 4.0%).

Despite a high clinical aggressiveness of tumors, long-term results of their treatment appeared to be quite favorable. The relapse-free survival rate for 5 years was 95.7%, for 10 years - 92.5%, and for 15 years - 79.4%. Taking into account the censored observations, the cumulative five-year survival rate according to the Kaplan-Meier method was 99.1%, the ten-year rate was 98.9%, the fifteen-year rate was 98.9%.

Conclusions

  1. The increased incidence of papillary thyroid carcinoma among the population of Ukraine is the only proven medical consequence of the Chornobyl disaster. Currently, the WHO experts determined the best formulation of the concept of “radiation-induced thyroid cancer”. One can say that it is not a special nosological form of the disease. Thyroid cancer is a registered medical effect of the nuclear accident at the Chornobyl Nuclear Power Plant, determined by a combination of clinical, epidemiological and morphological factors.

  2. The risk of the development of thyroid carcinoma in individuals affected in childhood due to the Chornobyl accident will persist for a long time, and the performance of permanent thyroid screening of this population group will allow identifying the disease at the early stages of its development.

  3. In case of preoperative cytologic diagnosis of “thyroid carcinoma” in patients who were children at the time of the Chornobyl accident, it is mandatory to perform total thyroidectomy in combination with preventive central neck dissection (level VI lymph nodes) regardless of the degree of tumor spread. Modified lateral neck dissection is indicated in case of confirmation of metastases. The performance of thyroidectomy reduces relapse proportion by 2.5 (3.8%) times compared to organ-saving surgery (9.7%).

  4. Further ablative radioiodine therapy allows evaluating the effectiveness of treatment according to the level of serum thyroglobulin and antibodies thereto, and early detection and surgical removal of iodine-refractory metastases does not affect survival rates.

Prospects for further research

Further studies will make possible to determine the main clinical, cytomorphological, radiological, biochemical factors of risk stratification allowing us to individualize diagnostic and treatment protocol for papillary thyroid carcinoma.

References

1 

Dovidnyk osnovnykh pokaznykiv diialnosti endokrynolohichnoii sluzhby Ukraiiny za 2015 rik. Endokrynolohiia. 2016;21(1):40.

2 

AE Kovalenko, IV Komissarenko. Protokol diagnostiki i lecheniya uzlovykh form zoba u postradavshego ot radiatsiyi naseleniya Ukrainy. Endokrynolohіia. 2012;17(4):37-43.

3 

AE Kovalenko, MYu Bolgov, PP Zinych, IS Suprun. Profilakticheskaya tsentralnaya dissektsiya shei pri papillyarnykh tireoidnykh kartsynomakh (obzor literatury i sobstvennye issledovaniya). Endokrynolohіia. 2014;19(2):141-148.

4 

BH Lang, SH Ng, LL Lau, et al. A systematic review and meta-analysis of prophylactic central neck dissection on short-term locoregional recurrence in papillary thyroid carcinoma after total thyroidectomy. Thyroid. 2013;23(9):1087-1098. doi:10.1089/thy.2012.0608

5 

MA Adam, J Pura, L Gu, et al. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann Surg. 2014;260(4):601-605. doi:10.1097/SLA.0000000000000925

6 

Y Zhao, Y Zhang, XJ Liu, et al. Prognostic factors for differentiated thyroid carcinoma and review of the literature. Tumori. 2012;98(2):233-237.

7 

M Tronko, T Bogdanova, I Komisarenko, A Kovalenko, et al. Thyroid cancer in Ukraine after the Chornobyl catastrophe: 25-year experience of follow-up. In: M Nakashima, N Takamura, K Suzuki, S Yamashita, editors. A New Challenge of Radiation Health Risk Management. Proc. of 6th Intern. Symp. of Nagasaki University Global COE Program "Global Strategic Center for Radiation Health Risk Control". 2012:39-64.

8 

M Tronko, T Bogdanova, V Saenko, et al. Thyroid cancer in Ukraine after Chornobyl. Dosimetry, epidemiology, pathology, molecular biology. Nagasaki: IN-TEX; 2014. 174 p.

9 

FI Macedo, VK Mittal. Total thyroidectomy versus lobectomy as initial operation for small unilateral papillary thyroid carcinoma: A meta-analysis. Surg Oncol. 2015;24(2):117-122. doi:10.1016/j.suronc.2015.04.005



Copyright (c) 2017 A. Ye. Kovalenko, Yu. M. Tarashchenko

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


IFNMU Logo

Free counters!