Nodal metastasis is crucial for determining the stage of well-differentiated thyroid cancer (WTC) in patients older than 55. Well-formed thyroid follicular inclusions (TFIs) are occasionally encountered in the cervical lymph nodes (LNs) of patients with papillary thyroid carcinoma (PTC), and it is difficult to determine whether they are true nodal metastases or ectopic thyroid tissues (ETT). This study aimed to elucidate the impact of the expression of the DNA damage response molecule TP53-binding protein 1 (53BP1) using immunofluorescence (IF) as a biomarker to differentiate TFIs in cervical LN by comparing the mutation analyses of primary thyroid cancers. The data demonstrated the necessity for the differential diagnosis of true metastases from ETT among TFIs in cervical LNs. PTC-like nuclear features using hematoxylin–eosin staining combined with immunohistochemistry for conventional biomarkers of PTC, including BRAF^V600E protein, were most helpful in identifying metastatic follicular-patterned carcinomas. In conclusion, IF analysis of 53BP1 expression could be an excellent ancillary technique to distinguish metastatic carcinoma or ETT from TFIs in LNs, particularly in cases other than BRAF^V600E-mutated PTC.

Oncocytic follicular adenomas (FAs) of the thyroid are neoplasms of follicular cell origin that are predominantly composed of large polygonal cells with eosinophilic and granular cytoplasm. However, the pathological characteristics of these tumors are largely unexplored. Both the initiation and progression of cancer can be caused by an accumulation of genetic mutations that can induce genomic instability. Thus, the aim of this study was to evaluate the extent of genomic instability in oncocytic FA. As the presence of p53-binding protein 1 (53BP1) in nuclear foci has been found to reflect DNA double-strand breaks that are triggered by various stresses, the immunofluorescence expression pattern of 53BP-1 was assessed in oncocytic and conventional FA. The association with the degree of DNA copy number aberration (CNA) was also evaluated using array-based comparative genomic hybridization. Data from this study demonstrated increased 53BP1 expression (i.e., "unstable" expression) in nuclear foci of oncocytic FA and a higher incidence of CNAs compared with conventional FA. There was also a particular focus on the amplification of chromosome 1p36 in oncocytic FA, which includes the locus for Tumor protein 73, a member of the p53 family implicated as a factor in the development of malignancies. Further evaluations revealed that unstable 53BP1 expression had a significant positive correlation with the levels of expression of Tumor protein 73. These data suggest a higher level of genomic instability in oncocytic FA compared with conventional FA, and a possible relationship between oncocytic FA and abnormal amplification of Tumor protein 73.

Papillary thyroid carcinoma (PTC) is the most prevalent histological subtype of thyroid cancer. However, it remains unclear whether BRAFV600E, TERT promoter (TERT-p), and certain pathological markers, such as loss of polarity/loss of cell cohesiveness (LOP/LCC), tall cells, mitotic count, and Ki-67 labeling index (LI) in recurrent tumors, are associated with clinical outcomes in patients with PTC after reoperation for recurrent PTC. This study investigates the impact of BRAFV600E and TERT-p mutations on progression-free survival (PFS) after reoperation for recurrent PTC. Cox regression analysis was employed to identify parameters associated with PFS. During a mean follow-up period of 27 months after reoperation, 39 patients (21.3%) experienced disease progression. Coexistence of BRAFV600E and TERT-p mutations (double mutation: Dmut) was observed in 21.3% of patients. TERT-p, Dmut, LOP/LCC (≥10%), mitotic count (≥3 per 2 mm2), and Ki-67 LI were found to be significantly associated with disease progression in unadjusted analyses. In a multivariable analysis, these associations remained significant, with hazard ratios and 95% confidence intervals for TERT-p, Dmut, LOP/LCC, mitotic count, and Ki-67 LI being 5.98 (2.31–15.5), 5.44 (2.21–13.3), 6.81 (2.00–23.2), 5.05 (2.07–12.3), and 5.85 (2.48–13.7), respectively. Extranodal extension was associated with disease progression in both unadjusted and multivariable analyses. TERT-p, Dmut, Ki-67 LI, LOP/LCC, mitotic count, and extranodal extension were identified as independent risk factors for poor PFS after reoperation. Close surveillance following reoperation is recommended for patients exhibiting these factors.

Papillary thyroid carcinoma (PTC) is the most prevalent subtype of thyroid carcinoma, constituting 80-85% of all cases. The clinical challenges posed by PTC are further compounded by its steadily increasing global incidence. Primarily associated with mutations in BRAF V600E and the TERT promoter (TERTp), the aggressive clinicopathological features and poor prognosis of PTC are exacerbated when these mutations co-occur. The Ki67 labeling index (LI), which reflects the proliferation rate of tumor cells, plays a pivotal role in assessing cancer aggressiveness. However, research on mutations in PTC cases in Kazakhstan is limited. This retrospective study included 240 patients with PTC. DNA extraction and mutation screening, droplet digital PCR (ddPCR) analysis for BRAF/TERTp mutations and Ki67 immunohistochemistry were performed. Two-sided Fisher's exact test, the Mann-Whitney U test, Kruskal-Wallis test, analysis of variance for nonparametric data were used. In Kazakh PTC cases, BRAF V600E was common (68.3%) and aligned with the patterns observed in the Asian population. TERTp mutations co-occurring with BRAF V600E (4.7%) were associated with advanced age, larger tumor size, lymph node metastasis, higher cancer stage, and higher Ki67 LI (10%). This study sheds light on the prevalence of BRAF V600E and TERTp mutations in Kazakhs with PTC. The integration of Ki67 LI assessment and mutation analysis may be instrumental in predicting the aggressiveness of PTC and guiding treatment decisions in this population. Not applicable.

Background: Medulloblastoma is the most common malignant pediatric brain tumor, exhibiting significant genetic heterogeneity. Mutations in TP53 and CTNNB1 have been implicated in tumorigenesis, prognosis, and treatment response. However, their precise role in medulloblastoma remains incompletely understood. This study aimed to analyze TP53 and CTNNB1 variants in Kazakhstani pediatric medulloblastoma patients and assess their clinical significance. Methods: A retrospective analysis was conducted on 33 pediatric medulloblastoma cases from 2015 to 2023. Formalin-fixed paraffin-embedded (FFPE) tumor tissues were used for DNA extraction and Sanger sequencing of TP53 (exons 4, 5, 6, 7, 8) and CTNNB1 (exons 3, 4). Genetic variants were classified using ClinVar, ACMG guidelines, and AMP classification. Statistical associations between mutations, clinical features, and outcomes were assessed. Results: Among 28 successfully sequenced cases, seven TP53 variants were identified: c.214_215delinsTG (p.Pro72Cys), c.215_216delinsGT (p.Pro72Arg), c.300G>A (p.Gln100=), c.356C>G (p.Ala119Gly), c.357C>G (p.Ala119=), c.782+10C>G (splice-region), and c.817C>G (p.Arg273Gly). The p.Pro72Arg variant was significantly associated with metastasis (p = 0.008). The c.356C>G (p.Ala119Gly) variant, previously linked to Li-Fraumeni syndrome, was detected in one case. No variants were found in exons 3 and 4 of CTNNB1. Conclusion: This study highlights the role of TP53 mutations in medulloblastoma progression, particularly their association with metastasis. The absence of CTNNB1 mutations suggests that WNT pathway activation may be rare in this cohort. Further studies with larger sample sizes and functional validation are needed to clarify the prognostic and therapeutic implications of TP53 mutations in pediatric medulloblastoma. Введение: Медуллобластома — самая распространённая злокачественная опухоль головного мозга у детей, характеризующаяся значительным генетическим разнообразием. Мутации в генах TP53 и CTNNB1 играют роль в опухолеобразовании, прогнозе и ответе на лечение. Однако их точная роль при медуллобластоме до конца не изучена. Целью настоящего исследования явилось изучение вариантов TP53 и CTNNB1 у казахстанских детей с медуллобластомой и оценка их клинического значения. Методы: Был проведён ретроспективный анализ 33 случаев детской медуллобластомы за период с 2015 по 2023 год. Для экстракции ДНК и последующего секвенирования по Сэнгеру генов TP53 (экзоны 4, 5, 6, 7, 8) и CTNNB1 (экзоны 3, 4) использовались опухолевые ткани, фиксированные в формалине и залитые в парафин (FFPE). Генетические варианты классифицировались согласно базе данных ClinVar, рекомендациям ACMG и классификации AMP. Статистическая связь между мутациями, клиническими характеристиками и исходами была проанализирована. Результаты: Из 28 успешно секвенированных образцов были выявлены семь вариантов TP53: c.214_215delinsTG (p.Pro72Cys), c.215_216delinsGT (p.Pro72Arg), c.300G>A (p.Gln100=), c.356C>G (p.Ala119Gly), c.357C>G (p.Ala119=), c.782+10C>G (область сплайсинга) и c.817C>G (p.Arg273Gly). Вариант p.Pro72Arg показал значимую ассоциацию с метастазированием (p = 0.008). Вариант c.356C>G (p.Ala119Gly), ранее связанный с синдромом Ли-Фраумени, был выявлен в одном случае. В экзонах 3 и 4 гена CTNNB1 мутаций не обнаружено. Заключение: Данное исследование подчёркивает роль мутаций TP53 в прогрессировании медуллобластомы, в особенности их связь с метастазированием. Отсутствие мутаций в CTNNB1 указывает на редкость активации WNT-пути в данной когорте. Для более точной оценки прогностического и терапевтического значения мутаций TP53 при детской медуллобластоме необходимы дальнейшие исследования с большим числом пациентов и функциональной валидацией. Кіріспе: Медуллобластома — балалар арасында ең жиі кездесетін қатерлі ми ісігі болып табылады және генетикалық тұрғыдан алғанда айтарлықтай әртүрлілікпен сипатталады. TP53 және CTNNB1 гендеріндегі мутациялар ісіктің пайда болуына, болжамына және емге жауап беруіне әсер етуі мүмкін. Алайда, бұл мутациялардың медуллобластома кезіндегі нақты рөлі толық анықталмаған. Осы зерттеудің мақсаты — Қазақстандық балалар арасындағы медуллобластома жағдайларында TP53...

Introduction:Papillary thyroid carcinoma (PTC) metastasizes to cervical lymph nodes, where differentiation between metastatic carcinoma and benign thyroid follicular inclusions remains a significant diagnostic point. Previous studies have suggested molecular markers such as 53BP1, BRAF, and HMB1 for this purpose impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. [2,16]. We also previously showed that 53BP1 IF analysis is best for differentiation [19]. However, their routine application remains limited, especially in developing countries like Kazakhstan, due to expensive and technical difficultness. Reliable, cost-effective immunohistochemical markers applicable in routine practice are needed to improve diagnostic accuracy. Aim: To evaluate the diagnostic value of Cyclin D1 immunohistochemical expression in PTC lymph node metastases from benign follicular thyroid inclusions. Materials and Methods: Formalin-fixed, paraffin-embedded specimens from 18 thyroid cases were analyzed, in which included 16 PTCs, one follicular adenoma, and one adenomatoid goiter. Lymph node specimens were available for 13 PTC cases. Cyclin D1 immunohistochemistry was performed and evaluated based on nuclear staining intensity and the proportion of positive tumor cells. Expression patterns were correlated with clinicopathological features and BRAFV600E mutation status. Results:Cyclin D1 showed strong nuclear expression in 100% of primary PTCs and all corresponding lymph node metastases. One the other hand, in benign thyroid lesions and benign intranodal follicular inclusions expression of CyclinD1 was absent. Cyclin D1 positivity expression was observed across all tumor stages, including all tumor stages with lymph node metastases. A strong association with BRAFV600E mutation was identified, although Cyclin D1 expression was also defined in a BRAF wild-type case. Conclusions:Cyclin D1 is a very sensitive and specific immunohistochemical marker for papillary thyroid carcinoma. Its consistent expression in metastatic PTC and absence in benign intranodal thyroid tissue support its utility as a reliable adjunct marker for lymph node evaluation, particularly in diagnostically challenging cases. Введение: Папиллярный рак щитовидной железы характеризуется высокой частотой метастазирования в регионарные шейные лимфатические узлы, при этом дифференциальная диагностика метастаза остаётся значимой клинической и морфологической проблемой. В предыдущих исследованиях были предложены различные молекулярные маркеры, включая 53BP1, BRAF и HMGB1, для оценки прогностического значения и определения метастатического потенциала дифференцированной карциномы щитовидной железы [2,16]. В частности, анализ иммуннофлуоресцентной экспрессии 53BP1 продемонстрировал высокую диагностическую эффективность и перспективность в дифференциальной диагностике метастазов [19]. Однако широкое внедрение данных методов остаётся ограниченным, в развивающихся странах, включая Казахстан, что обусловлено высокой стоимостью исследования и необходимостью специализированного оборудования. В связи с этим сохраняется необходимость достижимых иммуногистохимических маркеров. Цель: Оценить диагностическую значимость иммуногистохимической экспрессии Cyclin D1 для дифференциальной диагностики метастазов и доброкачественных фолликулярных образований в лимфатических узлах при папиллярном раке щитовидной железы. Материалы и методы: В исследование были включены формалинфиксированные парафиновые образцы ткани (FFPE), всего 18 случаев, из которых 16 папиллярный рак щитовидной железы, один случай - фолликулярной аденоме и один случай — аденоматозному зобу. Метастатазы регионарных лимфатических узлов были выявлены в 13 из 16 случаев папиллярного рака щитовидной железы. Иммуногистохимическое исследование Cyclin D1 проводилось с оценкой уровня экспрессии на основании интенсивности ядерного окрашивания и доли позитивных опухолевых клеток. Полученные результаты были сопоставлены с клинико-патологическими характеристиками пациентов, включая возраст, пол, стадию опухоли и наличие метастазов. Результаты: Cyclin D1 показал выраженную ядерную экспрессию во всех (100%) первичных опухолях папиллярного рака щитовидной железы, включённых в...