Prognostic markers in medullary thyroid carcinoma

Aim: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that accounts for 2% of thyroid tumors. The clinical course of the disease is usually aggressive and the only treatment method is total thyroidectomy and central neck lymph node dissection. Despite aggressive surgical treatment, the incidence of recurrence and metastasis is quite high. Additional prognostic factors need to be investigated further in order to aid systemic therapy and postoperative follow-up strategies. It is known that the expression status of the Bcl-1 gene and p27 molecule and the Ki-67 cell proliferation index are associated with metastasis potential and prognosis in many tumors. In our study, it is aimed to reveal the relationship between the immunhistochemical expression status of bcl-1, p27 and Ki-67 proliferation index and lymph node and distant metastasis in medullary thyroid carcinoma. In addition, the relationship between metastasis and some histomorphological and demographic findings such as age, gender, tumor size, tumor margins, mitosis rate, presence of necrosis, desmoplastic reaction, amyloid, capsule invasion, lymphatic and vascular invasion, and extrathyroidal extension will be evaluated. Materials and methods: The digital archive records of Istanbul University, Istanbul Faculty of Medicine, Department of Pathology is searched for the cases that were diagnosed as medullary thyroid carcinoma cases, between the years 2000 and 2020. From these records, cases with regular clinical follow-ups and whose blocks could be accessed were selected, and a study group consisting of 95 patients was formed. Immunohistochemical analyzes were performed with Bcl-1, Ki67 and p27 antibodies on the sections prepared from the formalin fixed paraphine embedded tumor blocks. Histopathological parameters were re-evaluated in hematoxylin-eosin stained sections. Follow up data of the cases were retrieved from the medical records of relevant clinics. Results: Lymph node metastasis was observed in 51 of 95 cases in the study group, local-regional recurrence was observed in 22, distant metastasis was observed in 17 cases, and death due to disease was detected in 13 cases. According to the grading system referred in the WHO 2022 Endocrine System Tumor Classification, 61 (64.2%) of the cases were determined as low grade and 34 (35.8%) as high grade. The grade was found to be prognostically 4 significant. It was observed that lymph node metastases and distant metastases were more frequent and survival was lower in cases with necrosis. A significant correlation was found between lymph node metastasis and male gender, tumor diameter greater than 4 cm, positive surgical margins, fibrosis, extrathyroidal extension, high grade, necrosis, lymphatic invasion, vascular invasion, and distant metastasis. It was observed that lymph node metastasis and distant metastasis were more frequent in cases with a Ki67 proliferation index of ≥5% than in cases with a Ki67 proliferation index of <5%. It was also significantly associated with reduced survival. No significant correlation was found between Bcl-1 immunohistochemistry and lymph node metastasis, distant metastasis and survival. Heterogeneous, weak-focal reaction was obtained in tumor cells with P27 immunohistochemical examination, and the antibody was not found to be reliable to be used in routine practice. Conclusion: The overall survival is lower in cases with fibrosis, extrathyroidal extension, positive surgical margins, necrosis, and lymphatic invasion. No correlation was found between age, tumor size, presence of amyloid and survival. Although survival was lower in male patients and in cases with vascular invasion, it was not statistically significant. When the cases were divided into two groups as high and low grade, grading was found to predict survival. It was determined that a Ki67 value above 5% significantly reduce survival. In multivariate analysis, the only independent prognostic factor predicting overall survival was found to be the presence of necrosis. No significant correlation was found between Bcl-1 immunohistochemistry and lymph node metastasis, distant metastasis and survival. The p27 antibody has not been found to be safe to be used in routine practice.