Comparative pathological characteristics of papillary thyroid carcinoma with second primary non-thyroid malignancies in the region affected by the Chernobyl accident.

The aim was to study the pathological features of papillary thyroid carcinoma diagnosed with or before second primary malignancy in patients exposed to post-Chernobyl exposure. The patients selected (n = 6559) were those exposed to radiation at the age of ≤ 18 years old and developed papillary thyroid carcinoma during the years 1990-2020. Of these, 2.1% (n = 140) had second primary malignancies. To compare the histopathological characteristics of papillary thyroid carcinoma in the group under analysis, 91% (n = 128) with sufficient data were included in further analysis. The control group was formed by matching patients with age at exposure to radiation, age at surgery, gender, and place of residence. Median age at exposure was 14 years old for both groups. Besides, no difference in tumour extension and histological features of papillary thyroid carcinoma was noted between patients with synchronous or metachronous primary malignant tumours. Nevertheless, the time lag to the diagnosis of papillary thyroid carcinoma was shortened in the group with metachronous when compared to patients with synchronous second primaries (p < 0.001). Independent differences between patients with second primaries and their matched peers included tumour size {OR (95%CI) = 0.89 (0.45; 1.04)}, multiple tumours {OR (95% CI) = 1.46 (0.86; 2.42)}, lymphatic vessel invasion (OR (95%CI) 0.92 (0.61; 1.53)), blood vessel invasion (OR (95%CI) 0.41 (0.10; 1.23) and presence of numerous psammomas (OR (95%CI) 0.73 (0.39; 1.31)). The possible influence of radiative iodine treatment for development of second primaries was analysed for the group of patients with metachronous malignancies using the same approach (84 patients were compared to 252 matched patients). Independent differences also included tumour size {OR (95% CI) 0.77 (0.45; 1.30)}, lymphatic vessel invasion {OR (95%CI) 0.75(0.43; 1.28)}, blood vessel invasion {OR (95%CI) 0.17 (0.01; 0.87)}. Besides, multiple tumours were revealed more frequently in patients with metachronous primaries (OR (95%CI) 1.92 (1.0; 3.62)). To conclude, patients exposed to Chernobyl irradiation with the development of papillary thyroid carcinoma and second primary malignancy have less biological aggressive pathological characteristics of their thyroid cancers. Accordingly, these patients were less frequently treated with post-surgical radioactive iodine. Thus, 131I-irradiation may have negligible impact on the development of second primaries.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus.

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

Second primary malignancies in patients with papillary thyroid carcinoma after effect of post-chernobyl irradiation: A risk analysis of more than two decades of observations.

BACKGROUND: Second primary malignancy in patients with papillary thyroid carcinoma after Chernobyl accident is an emerging problem. The aims of the study are to investigate the rates and distribution of second primary malignant tumours in Belarus survivors of post-Chernobyl papillary thyroid carcinoma and the cumulative rate of developing a second primary malignancy in a group of patients with metachronous second primaries. METHODS: Patients aged 18 or younger at the time of Chernobyl accident who were diagnosed with papillary thyroid carcinoma after 1986 were identified from the Belarus Cancer Registry. The clinical and demographic of these patients were analysed to correlate with the factors for the development of secondary primary cancer. RESULTS: Secondary primary cancer was detected in 1.8 % (119 of 6559) of the patients with papillary thyroid carcinoma. The cumulative incidence tended to rise with increasing age of the cohort and varied depending on the sex of patients. In female patients, breast carcinoma and genital tract carcinomas prevailed, in men patients - lymphoma/ leukaemia and the alimentary tract malignancies predominated. A significant excess risk was revealed for breast carcinoma in females, colon carcinoma in males, and the urinary system carcinomas in males (absolute excess risk [AER] = 3.23, 3.01 and 2.17 correspondingly). Overall, our results pointed to the increased risk of new solid primaries in females, males and both genders (AER = 3.31, 7.19, 4.28 correspondingly) as well as increase risk of lymphoid/hematopoietic malignancies in females and both genders (AER = 1.24) and leukaemia in male patients (AER = 1.45). CONCLUSION: Patients with papillary thyroid carcinoma after Chernobyl accident are at risk of secondary primary malignancy. Awareness and screening of secondary cancer is needed for patients with papillary thyroid carcinoma after Chernobyl accident.

Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case-control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial "misdiagnosis."

Factors affecting the approaches and complications of surgery in childhood papillary thyroid carcinomas.

BACKGROUND: The aim of the study is to analyse the factors related to permanent surgical complications in children and adolescents with papillary thyroid carcinoma treated by total thyroidectomy with central and bilateral neck dissections. METHODS: Children and adolescents aged ≤18-year-old at presentation with papillary thyroid carcinoma during the years 1988-2010 underwent thyroid and lymph-node surgeries (with a median follow-up of 19.6 years) were analysed for post-surgical complications. RESULTS: Permanent surgical morbidity occurred in 14% (n = 70) of patients who underwent total thyroidectomy as well as bilateral central and lateral neck dissections (n = 509). Factors associated with permanent complications included pN1 with extra-nodal extension, > 4 metastatic lymph nodes in the central neck compartment, presence of distant metastases and younger age of patients at surgery. Patients who received extensive surgery had better relapse-free survival rates (p < 0.001). CONCLUSION: Total thyroidectomy and bilateral central as well as lateral neck dissections for children and adolescents with papillary thyroid carcinoma was associated with substantial postoperative complications. Nevertheless, it is associated with better prognosis for young patients with thyroid cancer. Prophylactic compartment-oriented lymph node dissections to these patients could be the management protocol in experienced hands.

Optimizing treatment for children and adolescents with papillary thyroid carcinoma in post-Chernobyl exposed region: The roles of lymph node dissections in the central and lateral neck compartments.

There is lack of data to predict lymph node metastases in pediatric thyroid cancer. The aims are to study (1) the factors affecting the lymph node metastases in children and adolescence with papillary thyroid carcinoma in region exposed to radiation and (2) to evaluate the predictive significance of these factors for lateral compartment lymphadenectomy. Five hundred and nine patients with papillary thyroid carcinoma underwent total thyroidectomy and lymph nodes resection (central and lateral compartments of the neck) surgery during the period of 1991-2010 in Belarus were recruited. The factors related to lymph node metastases were studied in these patients. In the patients with papillary thyroid carcinoma, increase number of cancer-positive lymph nodes in the central neck compartment were associated with a risk to develop lateral nodal disease as well as bilateral nodal disease. Futhermore, positive lateral compartment nodal metastases are associated with age and gender of the patients, tumour size, minimal extra-thyroidal extension, solid architectonic, extensive desmoplasia in carcinoma, presence of psammoma bodies, extensive involvement of the thyroid and metastatic ratio index revealed after examination of the central cervical chain lymph nodes. The presence of nodal disease, degree of lymph node involvement and the distribution of lymph node metastases significantly increase the recurrence rates of patients with papillary thyroid carcinoma. To conclude, the lymph nodes metastases in young patients with papillary thyroid carcinoma in post-Chernobyl exposed region are common and the pattern could be predicted by many clinical and pathological factors.

Characteristics of cribriform morular variant of papillary thyroid carcinoma in post-Chernobyl affected region.

The aim is to study the characteristics of cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) in patients living in the radiation-affected area of Belarus. The clinical and pathological features of 35 patients with CMV-PTC from Belarus were studied and compared with those of conventional papillary thyroid carcinoma diagnosed in the same period. The patients with CMV-PTC were all females and were younger at presentation (mean age = 24) than those with conventional papillary thyroid carcinoma. Familial adenomatous polyposis (FAP) was identified in 20% of the patients with CMV-PTC. The majority of the CMV-PTCs (29/35; 83%) were staged as pT1 and were less advanced than conventional papillary thyroid carcinoma. There was no evidence of lymph node metastases or distant metastases. CMV-PTCs were positive for ß-catenin, APC (adenomatous polyposis coli) and p53 proteins. No psammoma bodies were identified on microscopic examination. Over a median follow-up of 9 years, all the patients were alive, and there was no cancer recurrence or mortality related to the thyroid cancer. To conclude, CMV-PTC in patients in the radiation-affected region behaves in an indolent fashion. They had distinctive features that are different from patients with conventional papillary thyroid carcinoma living in the same region.

Characteristics of young adults of Belarus with post-Chernobyl papillary thyroid carcinoma: a long-term follow-up of patients with early exposure to radiation at the 30th anniversary of the accident.

OBJECTIVES: Studies of thyroid cancer related to the Chernobyl accident have focused on children as they are the most vulnerable group with the highest risk of developing radiation-associated cancer. In contrast, our research aimed to look at the clinical and pathological features of patients with post-Chernobyl papillary thyroid carcinoma that were 2 years old or less at the time of the Chernobyl accident. DESIGN: The study subjects were patients (n = 359) aged 0 to 2 at the time of the Chernobyl accident and aged ≥19 years at presentation/surgery who were treated in Belarus for papillary thyroid carcinoma during the period 2003-2013. RESULTS: In conventional or oncocytic variant of papillary thyroid carcinoma, the prevalence of extra-thyroidal extension, nodal disease, infiltrative growth or lymphatic vessel invasion was above 50%. These features were less pronounced when compared to tall cell or diffuse sclerosing variants of papillary thyroid carcinoma. The highest frequency of central lymph node metastases was found in patients aged 1-2 years at exposure (P = 0·004). Subjects exposed in utero were characterized by absent/insignificant lymphocytic infiltration around the carcinoma (P = 0·025), predominance of conventional papillary architecture and an association with lymphocytic thyroiditis. CONCLUSIONS: A number of features were associated with this group of patients that were very young at the time of radiation exposure. In addition, the incidence and basic characteristics of adult papillary thyroid carcinoma varied depending on the types of exposure conditions.

Morphological Changes Induced by Bipolar Radiofrequency Ablation in Thyroid Nodules - a Preclinical Ex Vivo Investigation.

Introduction: Recently, radiofrequency ablation (RFA) has been increasingly used for the treatment of thyroid nodules. However, immediate morphological changes associated with bipolar devices are poorly shown. Aims: To present the results of analysis of gross and microscopic alterations in human thyroid tissue induced by RFA delivered through the application of the original patented device. Materials and methods: In total, there were 37 surgically removed thyroid glands in females aged 32-67 at presentation: 16 nodules were follicular adenoma (labelled as 'parenchymal' solid benign nodules) and adenomatous colloid goitre was represented by 21 cases. The thyroid gland was routinely processed and the nodules were sliced into two parts - one was a subject for histological routine processing according to the principles that universally apply in surgical pathology, the other one was used for the RFA procedure. Results: No significant difference in size reduction between parenchymal and colloid nodules was revealed (p>0.1, t-test) straight after the treatment. In addition, RFA equally effectively induced necrosis in follicular adenoma and adenomatous colloid goitre (p>0.1, analysis of variance test). As expected, tumour size correlated with size reduction (the smaller the size of the nodule, the greater percentage of the nodule volume that was ablated): r=-0.48 (p<0.0001). Conclusion: The results make it possible to move from ex vivo experiments to clinical practice.

Morphological and clinical presentation of papillary thyroid carcinoma in children and adolescents of Belarus: the influence of radiation exposure and the source of irradiation.

OBJECTIVE: The aims were to analyse the features of papillary thyroid carcinoma in a large cohort of children and adolescents in Belarus and to study the influence of radiation exposure as well as the source of irradiation on the morphological and clinical presentations of tumours. DESIGN AND PATIENTS: The clinical and pathological features of 1086 young patients (age range=4 to 18 inclusive, followed up for ≥18years) with papillary thyroid carcinoma diagnosed during the years 1990 to 2010 were reviewed. The patients were divided into three groups: "external radiation-related", "post-Chernobyl" (internal irradiation-related) and "sporadic". Besides, patients from "post-Chernobyl" cohort (n=936) were further divided into the three equal subgroups according to the dates of surgery, which were corresponding to the early (4-9years), intermediate (10-12years) and long (14-18years) latency periods. RESULTS: Patients in the "external radiation-related" group often showed extra-thyroidal extension in tumours sized ≤10mm (p=0.002). Distant metastases were more frequently (p=0.006) discovered in patients with papillary thyroid carcinoma in post-Chernobyl group (104 of 936, 11.1%) when compared to juveniles from other two groups. Lateral nodal disease and distant metastases were often noted in post-Chernobyl patients operated during the early and intermediate latency periods only. CONCLUSION: Young patients in Belarus with papillary thyroid carcinoma in the "post-Chernobyl" group differed in many clinical and pathological parameters from those in the "sporadic" group. "External radiation related" papillary thyroid carcinomas were distinguished from other two groups of carcinoma in more advanced local spread and more aggressive behaviour of micro-carcinomas.

Initial presentation and late results of treatment of post-Chernobyl papillary thyroid carcinoma in children and adolescents of Belarus.

BACKGROUND: The aim of this population-based study was to evaluate the clinical and pathological characteristics and outcome of papillary thyroid carcinoma (PTC) that have arisen in the Belarusian childhood population exposed to the radioactive fallout from the Chernobyl accident within a long-term period. PATIENTS AND METHODS: The long-term treatment results were investigated in 1078 children and adolescents (<19 years old) with PTC who were surgically treated during the years 1990 through 2005. RESULTS: Patients had high rates of metastatic PTC at presentation, with 73.8% of cases having lymph node involvement and 11.1% having distant spread. The most influential factor for lymph node metastases at initial treatment was lymphatic vessel invasion (P < .0001) and for distant metastases, lateral lymph node involvement (P < .0001). The overall survival was 96.9% ± 0.9% with a median follow-up of 16.21 years, and 20-year event-free survival and relapse-free survival were 87.8% ± 1.6% and 92.3% ± 0.9%, respectively. Patients had significantly lower probability of both loco-regional (P < .001) and distant relapses (P = .005) after total thyroidectomy (TT) and radioactive iodine therapy (RAI). For loco-regional relapses after TT, only RAI influenced the prognosis significantly (P < .001). For distant relapses after TT, the refusal to treat with RAI (hazard ratio [HR] = 9.26), vascular invasion (HR = 8.68), and age at presentation (HR = 6.13) were significant risk factors. For loco-regional relapses after non-TT, the principal risk factors were age less than 15 years old at presentation (HR = 5.34) and multifocal growth of tumor (HR = 5.19). For distant relapses after non-TT, the lateral neck metastases were the only unfavorable factor (HR = 9.26). CONCLUSION: The outcome of PTC both in children and in adolescents exposed to the post-Chernobyl radioiodine fallout was rather favorable. TT with RAI is recommended for minimizing loco-regional or distant relapses.

Clinical and pathologic features of "sporadic" papillary thyroid carcinoma registered in the years 2005 to 2008 in children and adolescents of Belarus.

BACKGROUND: A systematic analysis of the clinical and pathologic patterns of childhood "sporadic" thyroid carcinoma in Belarus, in the absence of the "Chernobyl radioactive iodine factor," has never been performed. The aim of this study was to establish the essential features of "sporadic" papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. METHODS: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. RESULTS: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). CONCLUSION: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

Computer-aided Image Processing of Angiogenic Histological.

UNLABELLED: This article reviews the questions regarding the image evaluation of angiogeneic histological samples, particularly the ovarian epithelial cancer. Review is focused on the principles of image analysis in the field of histology and pathology. The definition, classification, pathogenesis and angiogenesis regulation in the ovaries are also briefly discussed. It is hoped that the complex image analysis together with the patient's clinical parameters will allow an acquiring of a clear pathogenic picture of the disease, extension of the differential diagnosis and become a useful tool for the evaluation of drug effects. The challenge of the assessment of angiogenesis activity is the heterogeneity of several objects: parameters derived from patient's anamnesis as well as of pathology samples. The other unresolved problems are the subjectivity of the region of interest selection and performance of the whole slide scanning. KEYWORDS: Angiogenesis; Image processing; Microvessel density; Cancer; Pathology.