BUI DANG MINH TRI STUDYING CLINICAL CHARACTERISTICS, SUBCLINICAL, BRAF V600E GENE MUTATION AND RESULTS OF SURGICAL TREATMENT THYROID CANCER Specialization: Surgery Code: 9720104 SUMMAR
Trang 1BUI DANG MINH TRI
STUDYING CLINICAL CHARACTERISTICS, SUBCLINICAL, BRAF V600E GENE MUTATION AND RESULTS OF SURGICAL TREATMENT
THYROID CANCER
Specialization: Surgery Code: 9720104
SUMMARY OF THE THESIS OF MEDICINE
HA NOI – 2019
Trang 2VIETNAM MILITARY MEDICAL ACADEMY
Science instructor:
1 Assoc Professor Ph.D Mai Van Vien
2 Assoc Professor Ph.D Nghiem Duc Thuan
Critic 1: Professor Ph.D Le Ngoc Thanh
Critic 2: Assoc Professor Ph.D Le Dinh Roanh
Critic 3: Assoc Professor Ph.D Nguyen Huu Uoc
The thesis will be protected at the University-level Thesis Assessment
Council Meeting at: Military Medical Academy
on hours day month year 2019
The thesis can be found at:
- Vietnam National Library
- Library of Military Medical Academy
Trang 3INTRODUCTION TO THE THESIS
QUESTION
According to the Patient Survivor Association of Thyroid Cancer (2012), thyroid carcinoma is the most common endocrine cancer [1] Peterson E., De P., and Nuttall R (2012) stated [2] over the past 30 years, many countries have recorded a significant increase in the incidence of thyroid carcinoma, an average increase of 67% in women and 48% in men between 1973 and 2002 In the United State (US), according to the report
of Morrison S.A (2014) [3] the number of cases increased by 25% in 3 years, more than 56,000 people were diagnosed with new thyroid cancer
in 2012 and there are more than 200,000 new diagnoses worldwide in a year Patient's Association for the Survival of Thyroid Cancer [1] also thinks that about 70% of people diagnosed with thyroid carcinoma are aged between 20 and 55 and the male / female ratio = 7/3
Thyroid carcinoma is divided into two types including differentiation and non-differentiation Differentiation is dominant, including papillae, follicles and papillae Without differentiation, including the marrow, it can be indeterminate
According to Kaczka K., et al (2012) [7] in most cases, after surgery to remove the thyroid nucleus, the pathology of the thyroid gland is diagnosed by histology with conventional HE staining However, there are insufficient cases of subclinical information to distinguish between benign and malignant lesions if only regular HE staining is used Many studies of the authors Lange D (2004) [8], Demellawy D.E (2008) [9] and Fischer S (2008) [10] and their colleagues have shown that tissue culture is immune to the Antigenic markers - specific antibodies can help clearly distinguish and diagnose the thyroid disease
According to Cooper D.S (2009) [11], surgical removal of the thyroid gland is the most effective way to treat papillary thyroid carcinoma In addition, the great talent of Stack B.C (2012) [12], Lee
Trang 4B.J (2007) [13], Keum H.S (2012) [14] and colleagues also claimed that the dredging to the neck lymph nodes was Groups IIa, III, IV and
Vb are recommended when indicated to optimize treatment efficacy
The American Thyroid Association (2010) [15] and the British Thyroid Association [16] believe that thyroid carcinoma has a good prognosis if diagnosed early, treated properly and promptly However,
up to 7-10% of papillary thyroid cancer patients die within 10 years of being diagnosed
The author Lathief S (2016) [17] suggested that although most thyroid carcinoma can be determined before surgery by cytology, there are about 20 - 30% of cases cannot be determined by routine tests Many studies of authors such as Cheung C.C (2001) [18], Lange D (2004) [8], Nechifor-Boilă A (2014) [19], Demellawy D.E (2008) [9] and Wielganowicz M.J (2003) [20] have shown that immunohistochemistry with specific antigen-antibody markers can help
to better distinguish the pathological status of the thyroid gland In recent years, Liu C (2016) [21] and Liu X (2014) [22] have documented the role of BRAF V600E gene mutation in cancer diagnosis and prognosis papillary thyroid epithelium
1 Research objectives
These issues have not been systematically studied in Vietnam From the above fact, we carried out the thesis: "Research on clinical, subclinical characteristics, mutations of BRAF V600E gene and results
of surgical treatment of thyroid cancer" with the following objectives:
- Analysis of some clinical, subclinical, histopathological, immunohistochemistry, BRAF V600E mutations in patients with differentiated thyroid cancer
- Identify some relevant factors and evaluate the results of surgical treatment of differentiated thyroid cancer
2 New contributions of the thesis
From the study results, 102 patients with thyroid carcinoma
Trang 5were treated with surgery from 7/2013 to 6/2018 at Military Hospital
103, we found new contributions as follows:
2.1 Comments on clinical, subclinical, histopathological, immunohistochemistry, BRAF gene mutation V600E in differentiated thyroid carcinoma patients
- We find that the majority of women with thyroid carcinoma can
be differentiated and 4.67 times more than men, besides most patients hospitalized due to abnormal mass in the neck area before (accounted for 86.3%)
- Patients with metastatic lymph nodes are 100% dredged
- 84.3% of patients with thyroid carcinoma differentiated at T2 level, 11.8% had metastatic lymph nodes before surgery
- 52.0% of thyroid carcinoma in stage I; 48% in Phase II - III
- 99% of patients were positive for HBME-1, 100% were positive for CK19, 62.7% were positive for COX-2, 52.9% were positive for p53, 32.4% were positive for Ki67 and 89.2% positive for RET
- 60.8% of patients with thyroid carcinoma have BRAF mutation
at position T1799A (V600E) The rate of BRAF mutation was higher in the COX-2 positive group compared to the negative group (p <0.05) The rate of BRAF mutation was higher in the group with Ki67 negative compared to the positive group (p <0.05)
- There was no association between BRAF mutation, immunological markers of tumor characteristics, lymph node metastasis and Thyroglobulin concentration
2.2 Identify some relevant factors and evaluate the results of surgical treatment of differentiated thyroid carcinoma at Military Medical Hospital 103
- Without complications, or complications occur, tetani bout after surgery and bleeding after surgery account for a low rate of 1%
- Monitoring results after 1 month:
+ There are no patients with severe neurological damage, hypoparathyroidism
Trang 6+ Concentrations of FT3, FT4, Tg after surgery reduced and increased TSH levels indicated that the treatment was effective
- Follow up relapse: cumulative recurrence rate 11.78%
- When univariate analysis of prediction of BRAF V600E gene mutations and gender with risk of recurrence after surgical treatment and I-131 treatment, we found out among study patients:
+ Patients with BRAF V600E gene mutation have a higher recurrence rate
+ Female patients have a higher recurrence rate than male patients
- When univariate analysis of prediction of BRAF V600E gene mutations and gender with recurrence time after surgical treatment and I-131 treatment, we found out among study patients:
+ The average time of metastasis appears in the group of patients with the BRAF V600E mutation earlier
+ The average time of metastasis occurs in the group of male patients early
- Cox model analysis showed that patients mutating BRAF V600E gene would increase the risk of recurrence by 9.14 times (p = 0.04, log-rank test) compared to the group without mutation
3 The layout of the thesis
The thesis consists of 135 pages, in addition to the issues, conclusions and recommendations, the thesis consists of 4 parts: Chapter 1: Documents overview: 37 pages, chapter 2 - Subjects and research methods: 28 pages, chapters 3 - Research results: 30 pages, chapter 4- Discussion: 34 pages The thesis has 40 tables, 01 diagram,
12 pictures, 05 charts The thesis uses 125 references
Trang 7CHAPTER 1: DOCUMENT OVERVIEW
1.1 Clinical manifestations
1.1.1 Functional symptoms
According to the American Cancer Society (2014) [24] in the early stages, functional symptoms are often poor, of little value The majority of thyroid cancer patients come for examination because of the appearance of thyroid tumors Thyroid tumors may have long since remained unchanged but grew larger in a short time and harder Late stage or large, invasive tumor and often present with swallowing, shortness of breath, hoarseness Noncancerous cancers grow fast, large tumors stick to surrounding tissue, invasive trachea cause choking
1.1.2 Physical symptoms
- Thyroid tumors: can show one or more tumors in the thyroid gland with hard characteristics, clear edges, smooth or rough surface, moving according to swallowing rhythm In the late stage thyroid tumors are usually large, hard, fixed, on the surface of the red skin, ulcers or bleeding
- Thyroid tumors can be in one lobe, waist or both lobes
- Lymph nodes: majority of lymph nodes on the same side (possibly lateral or bilateral lateral lymph nodes), lymphadenopathy, supraclavicular, under the jaw, under the chin, thorny lymph nodes with solid, mobile, painless features Some cases have lymph nodes before the primary tumor is found According to the American Cancer Society [24] in young adults, neck lymph nodes appear to suggest thyroid cancer even if the thyroid gland is not palpable but actually thyroid cancer has been around for many years, some diseases The patient goes
to the hospital because of a distant metastasis, which can be detected by
a thyroid cancer
Clinical findings of thyroid tumors are sometimes difficult, especially with small tumors deep in the thyroid tissue and shown to be limited during clinical examination The neck cancers are an important sign
to help detect thyroid cancer, lymph nodes are concentrated on both sides
of the trachea, the outer margin, the inner and posterior lobe of the
Trang 8muscular dystrophy, epicardial pits, jaw angle In some cases, we can only touch the metastatic lymph nodes, but we have not felt the tumor, but actually there are very small tumors
1.2 Subclinical characteristics
- X-ray of the neck and chest area
Radiography is used in the early detection of thyroid diseases This method is especially valuable for those behind the sternum, when the physical examination in the posture of maximum neck resting does not feel the lower extremity of the tumor, chest radiography is indicated
to determine the posterior tumor Memory is needed
- Thyroid ultrasound is a very valuable diagnostic method for diagnosing thyroid morphology in general and is particularly valuable when distinguishing tumors with cysts, accurately assessing size, number, and limit
- I-131 thyroid and systemic radiography
Systemic I-131 scans are often used to detect recurrence and metastasis, but this test is only valid after surgery to remove the entire thyroid, by recording with I-131 after surgery Thyroid from 4 to 6 weeks, when TSH increases > 30 µIU/ml are eligible for testing To assess the results of treatment of remaining thyroid tissue destruction after surgery, it is recommended to record after 6-12 months after the previous treatment For differentiated thyroid carcinoma with lung metastases, this test High value in diagnosis Full body radiography is not only worth discovering but also has prognostic value
- Prick the cells with small needles
Small needle aspiration has reduced unnecessary thyroidectomy
1.3 Histopathological characteristics
1.3.1 Instant biopsy
Is a rapid diagnostic method of histopathology in surgery to diagnose thyroid cancer, is applied according to the cold cutting method Rapid diagnostic measures for histopathological lesions during surgery, help surgeons decide appropriate surgical methods, avoid unnecessary surgery for 20% of patients identified as cancer cells, Avoid re-surgery because repeated surgery is easy to cause parathyroid gland damage and laryngeal nerve According to Jozaghi Y (2013)
Trang 9[45], instant biopsy has an accuracy of 80-85%
1.3.2 Diagnosis of histopathology
- Papillary thyroid carcinoma
- Follicular thyroid carcinoma (oncocyte cell carcinoma, Hurthle cell)
- Thyroid carcinoma can be differentiated
- Thyroid carcinoma is not different
- Squamous cell thyroid carcinoma
- Mucous epidermal thyroid carcinoma
- Mucous epidermal thyroid carcinoma hardened with eosinophilia
- Mucous thyroid carcinoma
- Medullary thyroid carcinoma
- Rhombic cell cancer with thymus glandular differentiation (SETTLE)
- Mixed thyroid carcinoma of marrow and follicular cells
- Thymus glandular thyroid carcinoma (CASTLE)
1.4 Characterization of immune tissue
In most cases, diagnosis can be easily based on histological and clinical evidence However, in the diagnosis process sometimes encounter some difficulties:
- Limited tumors with minimal penetration of fibrous skin
- The lesions suspected of metastasizing from elsewhere
- Follicular variants and oncocytic cell variants of papillary thyroid carcinoma, medullary thyroid carcinoma
One or more combinations of antibodies have significantly improved the accuracy of the diagnosis of thyroid carcinoma Some immunological markers used in the diagnosis of thyroid carcinoma: RET, HBME - 1, COX - 2, P53, Ki67
1.5 BRAF V600E gene mutation:
According to the Kurtulmus N study (2016) [58] the gene mutation BRAFT1799A is a very valuable molecular marker in the diagnosis and monitoring of prognosis of thyroid carcinoma T1799A mutations only appear in thyroid carcinoma cells that are not found in benign thyroid cells and identify the BRAF T1799A mutation that will
Trang 10help limit the diagnosis of carcinoma The thyroid gland is omitted, improving the quality of medical examination and treatment, and monitoring and managing patients
1.7 Treatment of thyroid carcinoma
+ Facilitating the use of I-131 to treat the destruction of residual thyroid tissue, detecting relapse and treating regional lymph node metastasis and distant metastasis
+ Improve the sensitivity of Tg as a marker for survival and recurrence, metastasis of differentiated thyroid cancer
- Surgical methods: Currently, there are many different views
on surgical methods based on the following factors: histopathology, location, size, quantity, invasive extent of the tumor to the pulse organization around, metastatic lymph node metastasis, distant metastasis That cut a lobe or cut the entire thyroid gland, dredge neck lymph nodes
1.7.2 Adjuvant treatment after surgery
- Treatment with radioactive isotope I-131
Determination of therapeutic dose: The dose I - 131 for the treatment of thyroid tissue destruction after surgery, the therapeutic dose should be adjusted for children and the elderly, poor body isolation institute
- Chemical treatment: According to the American Cancer Society (2014) [24] chemicals are rarely used to treat thyroid carcinoma, especially differentiated thyroid carcinoma
Trang 11+ Criteria for selecting objects of reference group:
- Regardless of age and gender
- The results of histopathological examination after surgery are differentiated thyroid carcinoma
- Differentiated thyroid cancer, progressing in place, without distant metastasis
- No distant metastasis There is no coordinated severe chronic disease
- No other cancer combined
- Have enough medical records to store, record details of information to help the research in the form
+ Criteria to exclude patients
- Secondary thyroid cancer due to metastasis from other places
- Extensive invasive thyroid cancer whose surgery does not completely cut the entire thyroid
- Patients do not agree to participate in the study
+ Research method
Description of series, clinical interventions, cross-sectional descriptions, vertical monitoring, non-control Complete and intentional
Trang 12sampling All patients were carefully studied about history, medical history, clinical examination, doing laboratory tests according to a unified study medical record which was approved by the Scientific Council of the Military Medical Academy by
2.3 Processing and analyzing data
According to the medical statistical method, use SPSS 22.0 software Evaluate:
p>0.05: the difference is not statistically significant
p<0.05: the difference is statistically significant
2.5 Ethical issues in research
- Research subjects are voluntary
Trang 13Diagram 2.1 Research diagram
Surgery indicatiom
Thyroid tumor
Patients suspected of thyroid cancer
Clinical Thyroid inter sound
hormone-Conclusion I-131 treatment TNM stage
Evaluation
Path.Anatopy Im-chem.tests BRAF gene test Surgery
Perform FNA under the guidance of ultrasound
Instant biopsy