Literature Review
Clinical Study on the Treatment of Differentiated Thyroid Cancer
Yang, J. Reviewed by Zhao, Zhao, Department of Nuclear Medicine, China-Japan Friendship Hospital, Jilin University
The diagnosis and treatment of thyroid cancer have changed a lot in the past decade. This is mainly due to our in-depth understanding of this type of tumor and the emergence of new diagnostic and therapeutic methods. The diagnosis and treatment of thyroid cancer requires multidisciplinary assistance to complete. Without multidisciplinary consensus, differences in diagnosis and treatment occur, which will be extremely detrimental to the long-term outcome of patients, among which 131I is an important part of the treatment of differentiated nail cancer, and 131I treatment of DTC can reduce the recurrence and metastasis rates. In order to provide an understanding of the role of 131I in differentiated thyroid cancer, this article will review the therapeutic and side effect aspects of 131I for differentiated thyroid cancer.
Keywords: thyroid cancer, radiotherapy, iodine radioisotope
Thyroid cancer is a common malignancy of the endocrine system, accounting for 0.5%-1.5% of all malignancies. The prevalence of thyroid cancer varies regionally, with an annual incidence of 1-4 per 100,000 in most countries. The annual incidence of thyroid cancer in the United States is 4.5/100,000 (2.5/100,000 in men and 6.4/100,000 in women) 9.4/100,000 in people over 65 years of age, with a peak incidence of 30-39 years in women and 70-79 years in men [1]. The median age of onset was 55 years for males and 49 years for females, with females significantly earlier than males. The incidence of thyroid cancer has been increasing year by year for 21 years, and the increase in incidence is higher in women than in men [2]. The highest incidence of thyroid cancer is differentiated thyroid cancer (DTC), which accounts for 89%. The tumor cells are divided into two categories according to their origin. Papillary thyroid carcinoma, follicular thyroid carcinoma and undifferentiated carcinoma are among those that originate from follicular cells of the thyroid gland. In this article, we mainly review differentiated thyroid cancer (DTC).
I. Etiology
A variety of factors are thought to be associated with the development of thyroid cancer. Currently, only external irradiation of the neck during childhood is considered a risk factor associated with the development of thyroid cancer. The relationship between iodine and thyroid cancer is still debated. Most scholars believe that increased iodine intake cannot cause an increase in the overall incidence of thyroid cancer, but can lead to changes in the tissue type of thyroid cancer, i.e., an increase in the incidence of papillary thyroid cancer and a decrease in the incidence of follicular thyroid cancer. abnormal elevation of TSH and the production of various autoantibodies against thyroid tissue may lead to the development of thyroid cancer. It has been shown that thyroid cancer is the only epithelial malignancy that can be caused by specific chromosomal translocations, chimerism, and fusion genes, and that fusion proteins produced by rearrangement and hybridization of RET and PPARγ genes may play a key role in the development of thyroid cancer [3]. Other findings suggest that thyroid cancer is caused by the formation of PAX8-PPARγ fusion gene and mutations in BRAF, P53 and ras genes [4]. [4]. It has also been reported in the literature that 11 differentially differentiated thyroid cancers with TSH-R somatic mutations in different histological features were found [5].These tumors can be classified as follicular, papillary, or isolated thyroid cancers, and in many cases the tumors mimic the clinical phenotype of a high-functioning thyroid adenoma or toxic multinodular thyroid, and the diagnosis can only be made definitively after thyroidectomy or routine histological examination. Although active TSH-R mutations can overstimulate thyroid growth, the molecular mechanism of this transformation is unclear and needs to be further investigated.
Second, the pathological characteristics of DTC
1. Papillary thyroid carcinoma
The tumor forms papillae with many branches; the axis is fibrous tissue and blood vessels; the outer layer is covered with tumor epithelial cells; the cells are usually single-layered, with multiple layers between them; the cancer cells are mostly square, with uniform cytoplasm; the nucleus is large, and the nuclear chromatin is fine, so the staining is very light, called hairy glass-like nucleus; the interstitium may have calcification and sand granules.
2.Follicular thyroid cancer
(1) Highly differentiated: there are follicles and gliosis, the diagnosis mainly depends on the film infiltration.
(2) Moderately differentiated: the size of follicles and glial content vary greatly, and the cells have different degrees of interstitial changes, usually with less glial.
(3) Low differentiation: cancer cells are arranged into solid beams and cords, solid sheets, with less or no follicle formation and no gliosis.
III. Clinical introduction of DTC
Most patients with differentiated thyroid cancer come to the clinic with a neck lump without any clinical symptoms. Signs include neck nodules, neck thickening, and occasionally hoarseness. After physical examination of neck ultrasound and thyroid nuclear imaging suggesting suspicious malignant tissue, further pathological examination and cytological aspiration examination are performed to clarify the diagnosis. Questioning should include whether there is a family history, a history of childhood radiation exposure. Surveys in the general population have found that single nodules have a 5%-12% chance of malignancy and multiple nodules have a 3% chance of malignancy[6] . The sensitivity, specificity, and accuracy of the diagnosis of thyroid cancer were 90.6 %, 95.3 %, and 94.0 %, respectively, when combined with radionuclide 99mTc and 99mTc-MIBI imaging in women, elderly, and children [7]. Most of the patients are cured or survive for many years with the tumor, which is considered as a less malignant tumor and most of them have a good prognosis. However, some of these patients can recur after many years. The malignant potential of thyroid cancer is more complex than that of any other human tumor. The clinical manifestations and prognosis of each type of thyroid cancer vary greatly and are influenced by the treatment method, the patient’s gender, age, and whether the treatment is timely or not.
Treatment of DTC
1.Surgical treatment of DTC
According to the patient’s thyroid needle cytology examination and thyroid cancer metastasis, limited lobectomy of one side of the thyroid gland, subtotal thyroidectomy (removal of all thyroid tissue visible to the naked eye, leaving only the thyroid tissue of the laryngeal recurrent nerve into the cricothyroid muscle), total thyroidectomy (removal of all thyroid tissue visible to the naked eye), and cervical lymph node dissection are used [8].
2. Post-surgical treatment of DTC
Postoperative treatment of differentiated thyroid cancer includes radioactive 131I therapy and thyroxine replacement therapy. Foreign literature reports that postoperative 131 therapy supplemented with thyroxine replacement therapy can reduce the recurrence rate and improve the survival rate [9], and the selection of specific treatment methods should be based on different age, stage, metastatic site and other factors to choose the best individualized treatment plan. Thyroxine replacement therapy is performed for patients who have no residual thyroid tissue and metastases after surgery and have a very low likelihood of recurrence. For patients with primary tumors less than 1 cm, without peripheral invasion, lymphatic metastases, not growing outside the thyroid gland, and after near-total resection, 131I 1.11-3.7G-Bq therapy is administered. The dose is increased for those with recurrence and those with metastatic foci. Local lymph node metastatic lesions should be treated with oral 131I 3.7-4.44GBq supplemented with thyroxine replacement or suppression. For metastatic lung lesions, the oral 131I dose should be increased and 131I 5.5-7.4 GBq supplemented with thyroxine replacement or suppression therapy should be administered. For bone metastases, oral 131I 7.4-9.25 GBq supplemented with thyroxine replacement or suppressive therapy should be administered. For those who lack TSH receptors in the body and are insensitive to TSH regulation, thyroxine replacement therapy should be administered. After the treatment period, hTg , TgAb, 131I-WBS, 99mTc-MIBI imaging, and neck ultrasound are routinely checked regularly. If the above examinations suggest the presence of recurrence or metastases, oral radioiodine treatment should be given again according to the actual situation and other dispositions.
A multicenter clinical study found that radioactive iodine therapy should also be selective and will significantly benefit patients with a high risk of recurrence and AJCC stages III and IV[10] . Patients in the low recurrence group with AJCC stages I and II will have the majority of benefit[11].
Most scholars now believe that the combination of “surgery + 131I therapy + thyroid hormone suppression” for patients with DTC with aggressive biological behavior has achieved satisfactory results. At present, more and more doctors recognize the importance of radioactive iodine treatment for nail cancer, and the use of radioactive iodine to remove residual thyroid tissue is increasingly used in clinical practice.
Radioiodine ablation therapy or nail clearing therapy refers to the destruction of residual thyroid tissue visible to the naked eye after surgery, and also includes the removal of remaining microscopic lesions remaining in the thyroid tissue. The mechanism of radioactive iodine ablation therapy is the selective uptake of radioactive iodine through the thyroid follicle. Once the iodine has been collected, the radioactivity emits high-energy electrons through beta decay, resulting in the biological effect of ionizing radiation, which effectively destroys the lesion, thus achieving the goal of treatment.
Indications for nuclear therapy: ① distant metastasis; ② incomplete resection of tumor; ③ complete resection of tumor but there are the following: age > 45 years, high columnar papillary carcinoma with diffuse nodules, widely infiltrated follicular carcinoma, tumor beyond the envelope or lymphatic metastasis; ④ persistent elevation of Tg for more than 3 months after surgery. In contrast, low-risk patients with tumors less than 1. 5 cm and patients with a high residual thyroid gland are not suitable for nuclear therapy [12].
Theoretically, the benefits of residual thyroid removal are: 1. Removal of microscopic lesions in the residual body, reducing recurrence rate and mortality. The recurrence rate of differentiated thyroid cancer treated with surgery only was 32%, and the recurrence rate of surgical plus iodine removal of residual thyroid gland plus thyroxine treatment was 2.7%, and the mortality rate of papillary carcinoma was reduced from 11.7% to 3.1%. Follicular carcinoma mortality rate decreased from 12.5% to 2.7% [56].2, Tg( thyroglobulin) is more sensitive as a follow-up indicator. 3, Postoperative nuclear scan is more effective.4, Therapeutic dose scan is better and can detect lesions that cannot be detected by diagnostic dose [13].5, This facilitates early detection of recurrent and metastatic lesions by hTg or 131I-WBS and facilitates follow-up.6, Radioactive iodine will also emit γ-rays, and the iodine uptake is understood in vitro by detecting the radioactive distribution using a γ-camera [14].
Treatment with 131I to clear residual thyroid tissue requires high TSH levels, and many papers [15.16] suggest that TSH greater than 30 mu/L contributes to the uptake of radioactive iodine by the residual thyroid. Single exogenous TSH stimulation experiments suggest that maximum stimulation of thyroid cells can be achieved at TSH levels of 50-80 mu/L. Discontinuation of thyroxine tablets LT for 43 weeks can result in TSH of 30 mu/L or more in 90% of patients. Therefore, discontinuation of LT43-4 weeks is required for the administration of radioiodine therapy. For patients who cannot tolerate low thyroid, treatment can be switched to oral T3 for 2-3 weeks and then discontinued for T32 weeks, followed by measurement of TSH to determine if radioiodine therapy can be administered.
In order to facilitate the entry of radioactive iodine into the thyroid follicles, patients are usually advised to follow a low iodine diet for at least 2 weeks.
The patient’s thyroid hormone therapy is designed to prevent symptoms of hypothyroidism and to minimize TSH stimulation of thyroid cancer. High levels of TSH predispose to the recurrence of thyroid cancer. In endocrine treatment of thyroid cancer, TSH needs to be kept at low levels. Those with low risk of recurrence need to keep TSH at 0.1-0.5 mU/L; however, for patients with high risk of recurrence need to keep it below 0.1 [17]. Some scholars recommend that TSH suppression below 0.1 mU/L can improve prognosis, but it can lead to accelerated bone loss and also cardiac dysrhythmias and cardiac insufficiency [18].
It is still controversial whether 131I therapy is needed after surgery for papillary thyroid microcarcinoma (PTMC papillary thyroid microcarcinoma) Most scholars believe that 131I should not be routinely applied because he can neither reduce the recurrence rate of the tumor nor improve the survival rate, Dietlein [ 19] and some other scholars believe that postoperative oral 131I for papillary thyroid microcarcinoma can reduce the scope of surgery and decrease the risk of surgery.Dietlein treated 22 patients with multiple primary carcinoma foci of papillary thyroid microcarcinoma with bilateral subtotal thyroidectomy plus postoperative 131I, and none of them died from the thyroid lesion at an average follow-up of 65 months. Therefore, it is believed that postoperative 131I treatment for patients with microscopic carcinoma can reduce the trauma and complications of surgery. Radionuclide nail scavenging for residual thyroid is an option after surgery for papillary thyroid carcinoma in patients with almost complete thyroid gland resection without lymph node dissection and multicenter microscopic carcinoma prone to recurrence.
In conclusion, thyroid cancer has a good prognosis. The key to treatment is to choose the appropriate surgical method and postoperative treatment according to its pathological type and condition, and to treat those with cervical lymph node or pulmonary metastasis with active surgical treatment. The diagnosis and treatment of thyroid disease often involves multidisciplinary fields, and the identification of its benign and malignant nature before surgery, the determination of its risk level, and the proper application of radioactive iodine therapy after surgery are all problems that clinicians have to solve.
V. How to treat thyroid cancer with poor 131I uptake
This loss of 131I uptake ability is at least partially explained by the later observed decrease in NIS expression, which makes 131I therapy impossible. Extensive local tumor growth and metastasis in such patients later in life often prevent further surgical procedures, and when dedifferentiation progresses to the undifferentiated stage, most have a rather poor prognosis with high malignancy and increased morbidity and mortality [20].
The uptake of 131I by differentiated thyroid cancer is the basic rationale for the treatment of thyroid cancer. In the past, it was thought that there was a “sodium-iodine pump” in the thyroid follicular cell membrane that allowed extracellular iodine to enter the cell, but now it has been shown that this process is mediated by the sodium/iodine isotransporter in the basal cell membrane of the thyroid follicular cells. The main function of NIS is iodine uptake and concentration [21]. The identification of NIS and its gene provides a new approach and therapeutic direction for further radiation 131I treatment of thyroid cancer.
Among thyroid tumors, adenoma and differentiated carcinoma show different degrees of decreased NIS expression, while in undifferentiated carcinoma, there is almost no NIS expression, and thus their iodine uptake is significantly reduced or not at all. In differentiated thyroid carcinoma with negative 131I imaging of metastases, some of the thyroid carcinoma cells in the primary foci of patients express a lack of NIS gene, indicating that in these patients, metastases do not uptake iodine also with The successful cloning study of the NIS gene has contributed to the study of the molecular mechanism of reduced iodine uptake in thyroid cancer and its metastases. Franco A [22] et al. determined a series of thyroid cancer samples (19 papillary, 5 follicular and 2 undifferentiated carcinomas) by RT-PCR and found that NIS mRNA was not expressed in 5 of the 19 papillary carcinomas, I of the 5 follicular carcinomas and none of the 2 undifferentiated carcinomas. 4 of the 8 cases of differentiated thyroid cancer with negative systemic 131I scans had no NIS mRNA expression in the primary tumor. tumors had no NIS mRNA expression.
Smanik PA et al [23]. detected the expression of NIS mRNA in thyroid cancer and normal thyroid tissues by Northen blotting and found that the former was much lower than the latter. In these thyroid cancer tissues, 131I uptake was positively correlated with NIS expression, and NIS gene expression was variable to the same extent as the effect of radioiodine treatment, suggesting that NIS expression levels could be used as a predictor of the efficacy of 131I treatment for thyroid cancer.
Retinoic acid (RA), a bioactive metabolite of vitamin A, has been shown to inhibit cell proliferation and induce cell differentiation in a variety of tumors, such as acute promyelocytic leukemia, squamous skin cancer and head and neck tumors. The induction of differentiation by retinoic acid, which induces the reversal of differentiation of thyroid cancer cells and their gradual differentiation to normal cells, thus restoring or enhancing their iodine uptake capacity, will help to improve the efficacy of radioiodine therapy. 5′-DI is the main enzyme affecting thyroid iodine metabolism, and the expression level of 5′-DI correlates with the degree of differentiation of thyroid cancer cells. The expression level of 5′-DI correlates with the degree of differentiation of thyroid cancer cells and is shown to inhibit the proliferation of thyroid follicular carcinoma cells and enhance iodine uptake [24].
In the literature [25], 15 cases of undifferentiated thyroid cancer were reported, including 5 cases of follicular carcinoma, 8 cases of papillary carcinoma, and 2 cases of mixed follicular papillary carcinoma. The iodine uptake of metastases, the size of metastases and serum thyroglobulin (Tg) levels were measured before and after ATRA-induced differentiation therapy. The results showed that in 15 patients treated with ATRA-induced differentiation therapy, the 131 I uptake was increased in 7 cases and the metastases were reduced in 7 cases; among the 12 patients whose Tg was measured, 4 cases (33%) had both decreased Tg, increased iodine uptake and reduced or unchanged lesions.
Simon D et al. used 13-cis-retinoic acid (13-cRA) to induce dedifferentiated thyroid cancer in a clinical study in which patients were given oral treatment with 1.5 mg・kg- 1・d-1 for six weeks, and follow-up showed reuptake of radioactive iodine in 4 of 10 patients [26].Koerber C presented a case of papillary thyroid cancer with local recurrence and distant metastases, and retinoic acid secondary A comparative study before and after treatment with vincristine revealed increased 131I uptake after secondary treatment with vincristine and confirmed significant tumor redifferentiation by cytological examination and molecular biology [27] . The growth, and metastatic potential of thyroid cells can be affected by retinoic acid, inducing thyroid re-differentiation. Data from all studies on NIS and iodine uptake suggest that RA can induce a resumption of NIS expression and that thyroid tumors may re-differentiate, at least to the extent of establishing a therapeutic approach that would restore or enhance tumor iodine uptake, especially allowing for re-treatment with 131I. These findings suggest that retinoic acid (RA) offers a novel means of inducing differentiation in poorly differentiated thyroid cancer in parallel with radioactive 131I therapy.
VI. Side effects of 131I treatment
1.Radiation thyroiditis
The residual thyroid gland is large in 20% of postoperative DTC patients, and the administration of 131I at an irradiation dose of 500 rad to such patients will lead to the occurrence of thyroiditis [28], but the administration of 30 mCi will not produce radiation thyroiditis [29], and the symptoms are mainly pain in the throat and neck, hyperthyroidism, and the duration of symptoms is less than one week, which usually do not need to be treated.
2. radioactive salpingitis
After 131I treatment, approximately 1/3 of patients develop acute and or chronic salpingitis [30]. Symptoms tend to occur within 24 hours of oral 131I treatment and are particularly likely to occur in patients with small residual thyroid glands given high-dose 131I therapy [30]. Chewing gum and drinking lemon juice 24 hours after taking 131I can be effective in preventing radiation salpingitis. Many patients develop painless swelling of the parotid glands, often occurring several months after 131I treatment, resulting from blockage of the parotid ducts; a salty taste is usually felt in the mouth when the parotid glands are pressed by hand or when saliva flows naturally, and is easily misdiagnosed as infectious mumps, which usually does not require treatment and improves spontaneously within a year. Some patients may also present with reduced taste sensation and occasional tongue pain for several weeks as symptoms persist [30].
3. Dry eyes and lacrimal gland obstruction
Recent studies have found that conjunctivitis and lacrimal gland obstruction occur in patients on oral 131I (6.66-5.55 MBq), occurring 3-16 months after oral 131I [31]. It has been reported in the literature that out of 563 patients, 3.4% presented with these symptoms [32]. Because there is no systematic diagnosis and follow-up, the actual percentage should be higher than 3.4%, which is probably the most serious side effect and often requires surgical treatment [32].
4. radiation sickness
Given at doses of 200 mCi or more, 2/3 of patients may experience mild radiculopathy, including headache, nausea, and occasional vomiting, often occurring 4 hours after dosing, with symptoms resolving after 24 hours. Rarely, it occurs in patients treated with low-dose 131I [33].
5. Acute tumor swelling or bleeding
This is the most serious acute complication, which is due to 131I treatment or TSH stimulation. If the metastasis occurs in the brain, spinal cord, or lungs, it will continuously lead to the appearance of other serious illnesses [34.35]. If metastases occur in bone, severe pain may also occur. Although the administration of corticosteroids can prevent these side effects, surgical procedures should be considered for those with solitary brain metastases and spinal cord metastases before taking 131I [36]. Vocal cord paralysis is likely to occur after 131I administration when a large amount of functional thyroid tissue remains and is close to the vocal cords [36].
6. Hematological changes
After conventional doses of 131I treatment, platelet and leukocyte reductions are mildly reversible and do not present clinical symptoms [37]. After particularly high dose administration, whole blood cells may decrease, which then requires blood transfusion therapy, but this is also reversible [38].
VII. Follow-up and testing after DTC nail clearance
1. serum thyroglobulin (hTg)
1.1, Serum hTg significance
Thyroglobulin is the only specific protein synthesized by the thyroid gland in the human body and is a 660 kD glycoprotein secreted by thyroid follicular epithelial cells. hTg is not only the main component of the follicular colloid that constitutes the cell, but also provides the substrate and storage reservoir for thyroid hormone synthesis. All normal human sera can detect hTg, which is a normal product of thyroid secretion. Under physiological conditions, the size of the thyroid gland is the main determinant of hTg levels, and the volume of the thyroid gland shows a significant positive correlation with serum hTg levels, i.e., the larger the volume of the thyroid gland, the higher the serum hTg level [39]. The normal value of hTg recommended by the standard thyroglobulin assay is 15 ng/ml [40]. When thyroid tissue is damaged, it is freed from the thyroid follicles and appears in peripheral blood. hTg has a biological half-life of 3-4 days, and serum hTg levels are low and stable 6-8 weeks after surgery. Certain scholars consider the detection of peripheral blood hTgmRNA levels as a reference value for the diagnosis of certain thyroid diseases [41].
Serum hTg originates from functional thyroid tissue and is influenced by several factors. hTg should not be present in the serum of patients with DTC after surgical removal and complete clearance of the thyroid gland by 131I. If hTg is elevated above normal, it indicates recurrence of thyroid cancer or distant metastasis.
hTg can be used as a tumor marker for follow-up of patients after thyroidectomy, but also for other patients, for example, once metastatic lesions are detected but no primary lesions are found, and patients with high suspicion of thyroid origin, then hTg is also a useful test. High levels of hTg suggest a tumor of thyroid origin. High levels of hTg suggest a tumor of thyroid origin. Normal levels exclude highly differentiated thyroid cancer derived from thyroid follicular cells. Furthermore, Spencer et al. suggested that hTg levels should also be measured preoperatively in DTC in order to obtain information about the function of the tumor in secreting hTg [42].
Although hTg is not the “gold standard” for the diagnosis of DTC recurrence or distant metastasis, it still has the most important significance in the prognosis of differentiated thyroid cancer (DTC) and monitoring the outcome. The elevation of serum hTg level is a definite sign of recurrence or metastasis after DTC surgery, and regular follow-up of serum hTg can help to determine the prognosis of DTC patients and monitor the effect of treatment. The secretion of thyroglobulin requires the stimulation of TSH, so it is necessary to suspend L-T4 therapy to allow TSH to rise before measurement to exclude false-negative results. It is now clear that the human hTg gene is located on the long arm of chromosome 8. TSH stimulates transcription of the hTg gene and increases hTg synthesis [44]. The sensitivity of hTg was found to be 88-97% and the specificity reached 100% in the follow-up and review of clinical DTC patients. In case of serum thyroglobulin autoantibody TgAb(I), if the preoperative serum hTg value is not elevated, it is possible that the tumor cells have a low degree of differentiation and low ability to secrete hTg, and postoperative monitoring when hTg(I) does not determine the absence of tumor recurrence; whereas a slightly elevated hTg value suggests tumor recurrence. If the serum hTg concentration of DTC patients is elevated before surgery, it suggests that the tumor tissue has a strong ability to secrete thyroglobulin, and the sensitivity of postoperative monitoring with hTg is high. Thyroglobulin can be used as an indicator of thyroid tumor diagnosis, prognosis, recurrence, and metastasis [45] . In postoperative differentiated thyroid (patients who have undergone total thyroidectomy or have been treated with radioactive iodine ablation). hTg follow-up during L-T4 replacement therapy can be influenced by a combination of residual thyroid tissue and TSH concentrations. When the TSH level is normal (or lower than normal), the serum hTg concentration is generally less than 2 μg/ml, which can exclude the possibility of functional recurrence or metastasis in the body; if the hTg concentration is greater than 2 μg/ml, the continuous increase of blood hTg in multiple follow-ups indicates the possibility of functional recurrence or metastasis in the body; or the gradual increase of TSH after the discontinuation of L-T4 stimulates the increase of blood hTg. If the hTg concentration is greater than 2ng/ml, the hTg elevation is not obvious, which may be related to the fact that some DTC tumor cells secrete hTg with unique epitopes, leading to changes in their biochemical characteristics and producing non-immunoreactive hTg. The antibodies in the assay only recognize a limited number of epitopes, which may cause false negative hTg. Alternatively, it may be related to the tumor secretory function, resulting in low amounts of secreted hhTg, which can also lead to false negatives. Brendel reported that metastases were found in 8.5 % of patients with serum hTg <3 μg/ L at therapeutic doses of 131 I - WBS [46]. Some authors have found that hTg is not as positive in the case of lymphatic metastases [47 ]. Because it is difficult to determine what level of hTg is normal after the remaining thyroid is cleared, some units still consider 15ug/L as normal, which may allow some low level hTg tumors to be missed.
Heemstra, Karen A. found that the highest diagnostic accuracy of hTg was achieved by measuring hTg values at 5 time points during DTC follow-up, before ablation, 6 months post-operative TSH suppression, 6 months post-operative TSH stimulation, 2 years post-operative TSH suppression, and 5 years post-operative TSH suppression, respectively. The highest diagnostic accuracy of hTg was measured 6 months after treatment in the presence of TSH stimulation (cut-off point for hTg values was 10 μg/l; sensitivity was 100%, accuracy was 93%). The hTg values in the TSH-stimulated state were independent predictors of death before 131I ablation treatment, and six months after the procedure [48]. They found that the reference cut-off point for hTg was dependent on the time point in follow-up, which is also an important finding. Another study found that hTg is a useful diagnostic tool in the follow-up of patients with differentiated nail cancer after treatment, and that improving the clinical value of hTg results can lead to early detection of recurrent lesions, suggesting optimal use of the rh-TSH stimulation assay [49].
1.2 Factors influencing the determination of hTg
The monitoring of blood hTg levels is influenced by several factors: 1) different assay methods; 2) TSH levels; 3) TgAb levels; 4) hTg heterogeneity.
1) Influence of different assay methods on hTg measurement
The intra-batch variation (CV %) of CL IA and RIA were 3.0 % and 10.0 %, and the inter-batch variation (CV %) was 3.9 % and 15.0 %, respectively. The inter-batch variation (CV %) was 3. 9 % and 15. 0 %, respectively. However, the correlation between the two methods was good [50] . Electrochemiluminescence immunoassay (ECLIA) has the advantages of high detection sensitivity, wide detection linearity, small amount of specimens, and short detection time. It also has the advantages of automation of operation, shorter measurement time, wider measurement range, and longer effective use period of reagents, which is the direction of development of in vitro analysis. It is one of the fastest developing and popularized immunoassay methods at present. In addition, the continuous results of the series can be disrupted by the laboratory changing the method of detection of hTg/TgAb during the follow-up of DTC [51] .
2) Effect of TSH on hTg determination
Because the ability of thyroid tissue to synthesize hTg is TSH-dependent, although it has been suggested that hTg secretion by thyroid cancer tissue is not controlled by TSH, it is still more likely that the absence of detectable hTg at TSH ≥30 mIU/ L is considered disease-free. In patients receiving exogenous thyroxine replacement therapy, peripheral blood thyroglobulin concentrations are then measured by immunoassay. The sensitivity of detection may be reduced by about 40%. In order to achieve a high sensitivity of detection, thyroid hormones need to be discontinued to activate TSH [52] .
3) Effect of TgAb on hTg determination
The presence of high titers of hTg antibodies in about 20% of patients may interfere with the analysis of blood hTg monitoring results, resulting in false-negative hTg monitoring results [53]. postoperative blood TgAb levels > 100 IU/ml in patients with DTC significantly affect the blood hTg monitoring results, resulting in low hTg testing results. The presence of antibodies to the patient’s blood hTg needs to be taken into account in the follow-up [54].
4) hTg heterogeneity
Due to heterogeneity and other reasons, the protein form of thyroglobulin can vary from patient to patient and may not be fully recognized by traditional antigen-antibody binding immunoassays. This can lead to abnormal test results.
In conclusion, the current assay is influenced by many factors, and the development of a follow-up assay for hTg that completely excludes interference is a hot issue in recent years.
2.Serum thyroglobulin antibody (TgAb)
For patients with recurrent DTC or surviving with tumor whose hTg cannot be measured, a persistent increase in blood TgAb can also be a useful marker of tumor recurrence, so regular testing of TgAb is of high value for this group of patients [55]. In patients with DTC, TgAb is present in the serum of 20% of patients, and patients with TgAb(+) before thyroid surgery and a gradual decrease in TgAb concentration after surgery (in L-T4 replacement) is a sign of good prognosis; on the contrary, patients with no significant change or persistent elevation in serum TgAb concentration are predictive of the persistence or recurrence of the lesion. We observed that among 34 patients with thyroid cancer with TgAb (+), 26 cases with TgAb turning negative during follow-up were free of metastases or residual cancer; 5 cases with increased antibody titers were confirmed to have metastatic cancer; the other 3 cases with no significant change in antibody titers were found to have residual tumors.
3 Whole-body 131I scan at therapeutic dose (RxWBS)
It is known that whole-body 131I scan at diagnostic dose can detect residual thyroid and functional metastatic lesions in vivo.RxWBS can detect 20% more lesions than whole-body 131I scan at diagnostic dose and change the stage of tumor. It facilitates further treatment.