As the most common endocrine malignancy, incidence rates of TC have increased annually. PTC is most often insidious in onset and its clinical presentation is not obvious and with non-specific symptoms. Therefore, PTC tends to cause misdiagnosis or missed diagnosis. The evaluation ability of preoperative imaging examination, such as active US surveillance of the thyroid and neck lymph nodes, is limited.
Aggressive histological subtypes such as hobnail, tall-cell, solid, columnar-cell variants and diffuse sclerosing, and a rapid Tg level doubling time mean a higher frequency of lymph node metastasis. Recurrent TC is divided into local recurrence and regional recurrence, which include central compartment recurrence (primary or nodal recurrence), lateral neck recurrence (nodal lesions), and distant recurrence. Lymph node metastasis determines the scope of surgery. Total thyroidectomy is regarded as the standard surgical treatment. However, lobectomy alone does not reduce OS. Due to the lack of prospective randomized studies, it is very difficult to regard the management of recurrent/persistent lymph node metastases. Removing the nodes in areas of vital structures may help to prevent de novo distant metastases, but it has not been proven18.
Neck high-resolution ultrasound and serum thyroglobulin (Tg) assays are the mainstays of PTC follow-up. Experienced ultrasound physicians can improve the detection rate of abnormal cervical lymph nodes. However, non-invasive imaging assessment of lymph node metastasis of TC is a substantial operator dependency. Despite the consistent prediction of malignancy progress, micrometastasis of lymph nodes may also be misdiagnosed. What’s more, deep lymphonodus acoustically shadowed by air and bone may result in unsatisfactory visualization. Increasing Tg levels are highly suspicious for persistent/recurrent PTC. As a sensitive marker for the presence of thyrocytes, serum Tg cannot discriminate between malignant and normal cells, which results in false-positives in detectable values and high negative predictive values at undetectable levels. To avoid interference with Tg assays, it is necessary to assess serum TgAb concomitantly to avoid false-positive results. TSH suppression (serum level < 0.1 µU/mL) is recommended for PTC patients. Levothyroxine treatment inhibits the growth of PTC cells, and supplements thyroid hormones in the body. On the one hand, long-term low levels of TSH may aggravate the cardiac load and myocardial ischemia, and cause arrhythmia. On the other hand, it increases the incidence of osteoporosis (OP) in postmenopausal women.
Radioactive iodine therapy can irradiate possible foci of neoplastic cells and then reduce the recurrence risk to achieve the purpose of treating persistent or recurrent diseases. Treatment with high RAI activities is recommended for patients with a high risk of recurrence, while the predetermined RAI dose should outweigh the risks associated with its administration, which include diminished QoL and adverse events (AEs)19. Nevertheless, treatments for recurrent and metastatic RAIR-DTC were limited. 4 One-third of PTC patients are RAI-refractory. RAI refractoriness occurs in around 60ཞ70% of metastatic TCs. 10-year overall survival is < 50% in RAIR-DTC patients with distant metastasis. There are no curative drug treatments for RAI-R TC at present, At present, 2 multikinase inhibitors (MKI) (sorafenib and lenvatinib) are the first-line treatment of advanced RAIR-DTC patients. MKIs are accompanied by side effects, such as hypertension, diarrhea, weight loss, fatigue, anorexia/nausea, mucositis/stomatitis, proteinuria, skin rash, alopecia, and so on. Owing to resistance mechanisms, many targeted drugs have no significant impact on improving the overall survival rate for this disease. As associated with a longer progression-free survival time and improved local disease control, external beam radiotherapy (EBRT) can be considered in case of inoperable primary or locally recurrent TC and recurrent lymph node metastases after repetitive surgery. But it may cause radiation fibrosis and respiratory dysfunction20. Ultrasound-guided fine-needle aspiration cytology (FNAC) improved the accuracy in the preoperative diagnosis of suspicious LNM. The predictive value of FNAC is still limited in subjects with cytological features of the suspicious metastatic lymph node. FNAC is heavily dependent on the technical experience of the operators. Inadequate FNA sampling can lead to the failure in cytological diagnosis. Repeated aspiration can be dangerous because it may lead to an invasive wound. As an invasive method, it may increase the potential of metastasis and finally lead to poor survival and prognosis. The extracted small cells or tissues fail to monitor dynamic tumor progression or represent tumor heterogeneity. Early differential diagnosis of PTC with lymph node metastasis is the focus of clinicians. Although the above preoperative assessments are helpful for lymph node metastasis, it is difficult to find micrometastasis. Accurate preoperative evaluation is crucial for the selection of surgical methods, especially for the scope of lymph node dissection. If the scope of lymphnode dissection is insufficient, metastatic lymph nodes will be omitted. On the other hand, preventive lymph node dissection may cause excessive diagnosis problems. To sum up, the treatment of TC faces many problems. It is necessary to study the clinical markers of metastatic TC.
In advanced thyroid cancer, some mutations in genes have been found with variable frequency, such as BRAFV600E, NRAS, RET, PIK3CA, and PTEN21. The combination of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E and telomerase reverse transcriptase (TERT) promoter mutations have a robust synergistic promoting effect on the aggressiveness of PTC22. The clinical value of some immunohistopathology markers such as Galcitonin, TG, CyclinD1, CK19, CD56, HMBE-1, p27, p21, and E-cadherin is limited and further studies are needed to support their usefulness. The utility of RNA sequencing and genomic alterations is a burgeoning field of advanced thyroid cancer. Recently, the use of liquid assays such as circulating tumor cells (CTCs), circulating tumor nucleic acids (ctDNA/ctNAs), extra chromosomal circular DNA (ecDNA), and tumor-derived extracellular vesicles have been reported23.
Our study identified plasma-derived exosomal hsa-miR-1226-5p, hsa-miR-145-5p, hsa-miR-1226-3p, hsa-miR-4745-5p, hsa-miR-6735-5p and hsa-miR-6821-5p as valuable diagnostic biomarkers for the early detection of PTC LNM, which may lay a preclinical foundation for the inclusion of routine blood examinations. In the present study, we demonstrated that high exosomal levels of hsa-miR-145-5p, hsa-miR-1226-3p, hsa-miR-4745-5p, hsa-miR-6735-5p, and hsa-miR-6821-5p and low expression of hsa-miR-1226-5p differentiate PTC patients with lymph node metastasis from those normal control samples. This innovative experimental result may potentially change the landscape of clinical detection and therapy for patients with lymph node metastasis, and potentially give patients affected by 131I treatment options that can prolong survival. Such a combined plasma and exosome signature may lead to the development of specific and sensitive biomarkers for early PTC lymph node metastasis diagnosis and for monitoring postoperative disease recurrence. Future studies with a larger number of PTC samples are necessary to assess the true specificity and sensitivity of this Ex- miRNAs signature. How to manage individual patients with persistent nodal or suspected recurrent PTC is challenging. This study may help to minimize the recurrence rates and need for reoperation and sustain a disease-free status.
Next, we will continue to compare the levels of miRNAs and assess their utility as potential PTC biomarkers related to lymph node metastasis using exosomes extracted from the plasma of individuals with PTC performed following total thyroidectomy and radical cervical dissection.