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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY VU THANH PHUONG STUDY ON CHARACTERISTICS OF LYMPH NODE METASTASIS AND TREATMENT RESULTS OF STAGE II AND STAGE III MELANOM[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY VU THANH PHUONG STUDY ON CHARACTERISTICS OF LYMPH NODE METASTASIS AND TREATMENT RESULTS OF STAGE-II AND STAGE-III MELANOMA Specialty: Oncology Code: 9720108 SUMMARY OF PhD THESIS IN MEDICINET HA NOI - 2023 THE STUDY IS COMPLETED AT HA NOI MEDICAL UNIVERSITY Mentor: Asso Prof Dr Nguyen Dai Binh Opponent 1: Opponent 2: Opponent 3: The thesis will be presented committee of Ha Noi medical university at Date ./ .20 The thesis could be found in: National Library Library of Hanoi Medical University THE THESIS INTRODUCTION Introduction Melanoma is a malignancy of melanocytes, or early metastases by lymphatic route into regional lymph nodes and veins Melanocytes are responsible for producing the pigment melanin, which is derived from the neural crest In the body, melanocytes are mainly distributed in the basal layer of the skin, about 90% The incidence in the world has been increasing steadily every year, from 4-6%, over the past few decades In Vietnam, the incidence is 0.3-0.4/100,000 population Due to the limited knowledge about this disease, the majority (82.8%) of patients came for examination and treatment at K Hospital in stages II and III The characteristics of lymph node metastasis are quite special compared to some other cancers, the disease often metastasizes and metastasizes quite early to regional lymph nodes Therefore, we focus on studying the lymph node metastasis of this cancer Besides, the factors affecting the treatment results have been reported in many studies abroad, including tumor location, disease stage, number of regional lymph nodes metastasized, histopathological type, tumor thickness, Clark invasion, satellite nucleus, tumor ulceration, stage of development, multiplication rate, tumor infiltrating lymphoma, tumor infiltrating lymph nodes In Vietnam, there are very few studies on Melanoma These studies only refer to the epidemiological, clinical, and histopathological aspects of Skin and Mucosal Melanoma, but have not fully evaluated the pathology, postoperative treatment results and some other prognostic factors affecting the survival outcome after surgery Therefore, we conducted this study to achieve the following two objectives: Comment on the characteristics of lymph node metastasis of stage-II and stage-III melanoma at National Cancer Hospital Evaluation of postoperative results and analysis of some factors affecting survival outcomes in the study group of patients New contributions of the thesis - Results on characteristics of lymph node metastasis: + Rate of regional lymph node metastasis 48.1% (no metastasis 51.9%, lymph node metastasis 13.3%, 2-3 lymph node metastasis 15.6%, >3 lymph node metastasis 19.2%) and intermediate lymph node metastasis 5.9% + The rate of regional lymph node metastasis is higher in the group of patients with some of the following factors: disease duration > months, tumor location in the soles of the feet, tumor background is keratinized skin and normal skin, ulcerative warts and skin ulcers, histopathology of apical and local moles, increased tumor thickness, increased Clark IV-V invasion level, vertical growth stage, peritumoral microsatellite nucleus , tumors with vascular infiltration, non-tumour-infiltrating lymphocytes, tumors with the increased mitotic rate and tumors with microscopic ulcers - Results after the radical surgery and some prognostic factors affecting the survival: + Large tumor resection and regional lymphadenectomy 87.4%, amputation or dissection and regional lymph node dissection 12.6%, microscopic cancer removal area 100%; skin defects need patching 31.1% + There are no cases of intraoperative mortality and postoperative time, and the rate of postoperative complications is low Recurrence in tumor or lymph node 8.1%, distant metastasis 52.6% Survival rate for years in total 53.1%, Survival rate for years without metastasis recurrence 39.4% + Poor prognostic factors affecting 5-year survival after surgery: tumor location in the soles of the feet, increased disease stage, increased Breslow tumor thickness, tumor histopathology was apical mole and locality, number regional lymph node metastasis increased, Clark invasion increased, microscopic tumor ulceration, tumor mitotic rate increased, tumor had vertical growth stage, non-tumor infiltrated lymphocytes, invasive tumor enter the circuit and have satellite cores around u + Two independent poor prognostic factors, strongly affecting the 5-year survival time after surgery: microscopic tumor ulceration and vascular invasion Thesis structure The thesis consists of 138 pages: Introduction: pages; Literature Overview: 43 pages; Research subbjects and methods: 18 pages, Research results: 29 pages Discussion: 43 pages; Conclusion: pages; Recommendations: page In the thesis, there are 22 tables, 25 charts, figures and illustrative diagrams The thesis uses 191 references, including documents in Vietnamese and the rest documents in English, including 132 new documents in the past 10 years Chapter LITERATURE OVERVIEW 1.1 Histological structure of the skin 1.1 Physiological functions of melanocytes Pigmentation cells are cells with the function of synthesizing and distributing melanin pigments, have polyhedral cytoplasm, long cytoplasmic dendrites interspersed with the intercellular space of keratinocytes, polyhedral eukaryotes , located in the middle or lower half of the cell The cytoplasm contains pigment granules, which are melanosomes, and the lumen contains the pigment melanin 1.2 Epidemiology and risk factors for melanoma 1.2.1 Epidemiology of melanoma Incidence of disease: The worldwide prevalence of melanoma is 3.8/100,000 population for men and 3.0/100,000 population for women Mortality Rate: In 2020, worldwide, an estimated 57,000 people will die from Melanoma, 0.7/100,000 population for men and 0.4/100,000 population for women 1.2.2 Risk factors for melanoma 1.3 Diagnosis of melanoma 1.3.1 Symptoms suggestive of diagnosis - For early melanoma detection, according to ABCDE rule: A (Asymmetrical shape): asymmetrical skin lesions B (Border irigularity): irregular margin of lesion C (Color variegation): there are many different colors D (Diamter greater than 6mm): lesion diameter ≥ 6mm E (Evolution): to expand or develop - In addition, based on the Glasgow criterion, there are standards (3 major and minor): the main criteria are to change the size, shape, and color Secondary criteria were diameter > mm, scabbing or oozing, pruritus or altered sensation, local inflammatory reaction 1.3.2 Tools for early detection of melanoma Examination of the superficial layers of the skin by means of optics (Dermatoscope), thermal imaging, tissue elastography, fiber diffraction 1.3.3 Early diagnosis of melanoma Early detection of lesions is essential and important Dermatoscope to examine the superficial layers of the skin 1.3.4 Definitive diagnosis of melanoma Based on clinical: significant changes in tumor according to ABCDE rule, or based on Glasgow criteria Based on histopathology: Hematoxylin - Eosin (HE) staining, immunohistochemistry with S-100, Melan-A and HMB-45 1.3.5 Diagnosis of the microscopic level, applicable to the tumor According to Breslow thickness classification According to the Clark scale of invasion 1.3.6 Diagnosis of TNM melanoma stage Classification T according to the regulations of AJCC, the 8th edition 2017 Classification N according to the regulations of AJCC, the 8th edition 2017 Classification M according to the regulations of AJCC, the 8th edition 2017 Disease staging according to according to the regulations of AJCC, the 8th edition 2017 1.4 Histopathological forms of melanoma - Superficial spreading melanoma - Nodular melanoma - Lentigo malignant melanoma - Acral lentiginous melanoma 1.5 Melanoma metastasis pathway 1.6 Features of regional lymph node metastasis of melanoma 1.6.1 Mechanism of regional lymph node metastasis from tumor 1.6.2 Gateway lymph node metastasis 1.6.3 Medial lymph node metastasis (metastasis during transport) 1.6.4 The nature of metastasis by lymph node 1.6.5 Rate of regional lymph node metastasis 1.7 Current melanoma treatment 1.7.1 Treatment of melanoma stage Treatment is surgery alone to remove the tumor and part of the normal tissue surrounding the tumor The margin of safety of the surgical margin from the edge of the primary tumor is 0.5 cm 1.7.2 Treatment of melanoma stage I Treatment with surgery alone is to remove the tumor and some of the normal tissue surrounding it The safety limits of surgical margins vary according to tumor thickness The safe margin of surgical margin from the tumor margin is 0.5 cm for tumors with a thickness of ≤ 1.0 mm, cm for tumors from 1.01 to 2.0 mm Sometimes, lymph node mapping and regional lymph node biopsies are done to check for cancer in the regional lymph nodes at the same time as surgery to remove the tumor If cancer cells are found in regional lymph nodes, regional lymph node dissection must be performed 1.7.3 Treatment of melanoma stage II Treatment with surgery alone to remove the tumor and part of the normal tissue surrounding the tumor The safety limits of surgical margins vary according to tumor thickness The safe margin of surgical margin from the tumor margin is cm for tumors thicker than 2.0 mm Sometimes, lymph node mapping and regional lymph node biopsy are done to check for cancer cells in the lymph nodes at the same time as the tumor removal surgery If cancer cells are found in regional lymph nodes, selective regional lymph node dissection is required 1.7.4 Treatment of melanoma stage III Surgery to remove the tumor and surrounding healthy tissue, the safe margin of surgery is 2cm from the tumor margin and regional lymph node dissection After surgery, adjuvant immunotherapy, single-drug therapy or in combination with immune checkpoint inhibitors (Nivolumab, Pembrolizumab or Ipilimumab), has been shown to significantly improve clinical outcomes 1.7.5 Treatment of melanoma stage IV and metastatic recurrence New therapeutic strategies such as immunotherapy, which use antibodies that bind to checkpoint inhibitors of T-cell activation, have demonstrated impressive efficacy CTLA-4 inhibitors such as Ipilimumab, anti-PD-1 antibodies such as Nivolumab and Pembrolizumab, as well as selective BRAF inhibitors such as Vemurafenib, Encorafenib, and Dabrafenib (used alone or in combination with inhibitors MEK inhibitors such as Binimetinib, Cobimetinib, and Trametinib), have demonstrated effective anti-tumor activity 1.8 Some prognostic factors of melanoma 1.8.1 Age group 1.8.2 Gender 1.8.3 Tumor anatomical location 1.8.4 Tumor thickness (breslow maximum thickness) 1.8.5 Clark microscopic invasion 1.8.6 Tumor histopathology 1.8.7 Number of regional lymph nodes metastasized 1.8.8 Disease stage 1.8.9 Satellite nucleus around microscopic tumor 1.8.10 Superficial ulcer of u 1.8.11 Development stage 1.8.12 Microfield Divisor Ratio 1.8.13 Tumor infiltrating lymphocytes 1.8.14 Tumor invades blood vessels 1.9 Research on melanoma in Vietnam and around the world In 2001, Dao Tien Luc published a study on clinical features, histopathology and some clinical prognostic factors of malignant melanoma Research has shown that Melanoma accounts for 86% and mucosal melanoma 14% The 5-year overall survival rate is 25% Factors with poor prognosis for postoperative survival were male, tumor location in the soles of the feet, clinical tumor ulceration, and advanced disease stage In 2017, Dao Thi Thuy Hang published a study on histopathological characteristics and some histopathological factors related to lymph node metastasis in Melanoma The study has shown a high rate of regional lymph node metastasis in the group of patients with nodular, apical mole, increased tumor thickness, increased Clark grade, microscopic tumor ulcer, microsatellite, and developmental stage Vertical growth, increase in multiplication rate, decrease in lymphocyte infiltration, and vascular infiltration The author did not study the prognostic factors affecting survival after treatment In 2015, Eggermont AM et al published a study of 951 patients with stage III Melanoma who had surgery, randomized to groups, one to Ipilimumab adjuvant therapy (n = 475) and one to follow-up after surgery alone (n = 476) Median follow-up was 2.74 years, with 528 recurrence-free survival (234 in the Ipilimumab group versus 294 in the surgery alone group) Median recurrence-free survival was 26.1 months in the ipilimumab group compared with 17.1 months in the surgery-only group (hazard ratio 0.75 with p < 0.05, i.e., 25% reduction) risk of recurrence) The 3-year recurrence-free survival rate was 46.5% in the ipilimumab group compared with 34.8% in the surgery-only group, with p < 0.05 In 2017, Jeffrey Weber et al published a study of 906 patients with stage III, IVA Melanoma who had surgery Randomized, double-blind, twogroup trial comparing the efficacy of the adjuvant nivolumab with ipilimumab Minimum follow-up period of 18 months, 12-month recurrence-free survival rate 70.5% in the adjuvant group with nivolumab and 60.8% in the adjuvant group with Ipilimumab, risk rate of disease recurrence 65 with p < 0.001, that is, a 35% reduction in the risk of recurrence The author found that the adjuvant Nivolumab had a much higher recurrence-free survival rate than Ipilimumab Chapter RESEARCH SUBJECTS AND METHODS 2.1 RESEARCH SUBJECTS The study included 135 Melanoma stage II, III patients who were treated with surgery alone at National Cancer Hospital - Criteria for selection of study patients + Being diagnosed with Melanoma by histopathology at K hospital + Being diagnosed with Melanoma without previous tumor removal surgery + Melanoma was determined histopathological type and tumor cell characteristics from surgical specimens on HE staining and immunohistochemistry slides + Classified as stage II, III according to the AJCC 8th edition of 2017 criteria + Treatment with surgery alone No other cancers + Do not have other chronic diseases with a close risk of death + There is full information about the condition of the patient after surgery through periodic re-examination - Exclusion criteria + There is no definite diagnosis by histopathology as Melanoma + Melanoma had surgeried at Hospitals another + Subcutaneous metastasis of unknown primary melanoma + Melanoma at other organs of the body 2.2 RESEARCH TIME The study was conducted from November 1, 2015 to June 30, 2022 at National Cancer Hospital 2.3 RESEARCH METHODS 2.3.1 Research design Retrospective and prospective cross-sectional descriptive study with longitudinal follow-up 2.3.2 Sample size and sample selection P (1 P ) n = 1 /2 x Z d n = Minimum number of patients, Z1 /2 = 1.96, p = 25%, infer that p is 0.25, q = 1- 0.25 = 0.75, d = allowable absolute error = 0.1 Substituting numbers into the minimum sample size is 72 patients The actual sample entering the study was 135 patients who met the above criteria 2.3.3 Variables, indexes 2.3.3.1 Variables and indexes to study characteristics of lymph node metastasis 2.3.3.2 Research variables and indicators to evaluate postoperative outcomes and analyze factors affecting Survival for years after surgery Research variables and indicators to evaluate postoperative outcomes Research variables and indicators to analyze factors affecting Survival for years after surgery 2.3.4 Techniques and tools for gathering information Techniques and tools for gathering clinical and laboratory information of patients before treatment Techniques and tools for gathering patient information during treatment Techniques and tools for gathering patient information after treatment 2.3.5 Criteria, evaluation criteria for grading - T-rating standard according to the regulations of AJCC, the 8th edition 2017 - N-rating standard according to the regulations of AJCC, the 8th edition 2017 - M-rating standard according to the regulations of AJCC, the 8th edition 2017 Pure selection criteria: - Melanoma disease is limited locally, locally, no distant metastases (stage II, III means any T, N0, N1, N2, N3 M0) - To undergo extensive surgery to remove the tumor or amputate, remove limb joints, and remove regional lymph nodes Description of the surgical method 12 Through 135 patients, it found that skin patching was not required 68.9%; skin-muscle flap with vascular pedicle 14.1%; patch skin swap positions 7.4%; patch skin 9.6% 3.3.1.3 Relation of intraoperative skin patch to tumor location Melanoma surgery has skin patches but depending on the location, the need is different Tumor locations in the soles of the feet and skin have a higher rate than those in the trunk, upper limbs, thighs, legs, head and neck (43.7% versus 30%, 23.8%, 21%, and 17.6% respectively), with p = 0.017 3.3.1.4 Postoperative mortality and complications 135 patients underwent surgery and monitored postoperative complications, uncomplicated 83.7%; postoperative bleeding 0.7%; wound infection 1.5%; complications of lymphedema 14.1% No patient died 3.3.1.5 Results of follow-up after surgery longest follow-up patients 114 months, shortest 32 months, average follow-up time 72 months, no patients with half-way information loss and complete information loss, patients followed-up ≥ 60 months is 96 patients (71.1%) Recurrence in tumor, in lymph node accounts for 8.1% 3.3.1.6 Monitoring the distant metastasis, distant metastasis location and average time to develop distant metastasis after surgery Follow-up periodically after surgery until the end of the study, distant metastasis after surgery 52.6% 3.3.1.7 The second treatment due to recurrence, distant metastasis 71 patients with distant metastatic recurrence were not actively treated: 52.1% refused treatment, 46.5% analgesia, re-surgery and 1.4% immunotherapy 3.3.1.8 Survival for years in full 13 Overall Survival rate for years 53.1% 3.3.1.9 Survival for years without metastasis recurrence The 5-year metastasis-free survival rate is 39.4% 3.3.2 Factors affecting survival for overall years 3.3.2.1 Survival by age group Survival rate for years in patients with age group < 60 is greater than in patients with age group ≥ 60 (59.9% vs 39.8%), p = 0.118 3.3.2.2 Survival for by gender Survival rates for years in male patients and female patients were almost the same (53.2% vs 53.0%), p = 0.963 3.3.2.3 Survival by tumor location Survival rates for years in patients with tumors on the soles of the feet were lower than in patients with tumors in the head, trunk, upper limbs, 14 and lower legs (37.4% vs 77.7%, 59.8%, 52.2% and 67.6% respectively), p = 0.04 3.3.2.4 Survival by disease stage Survival rate for years in stage II patients was much greater than in stage III patients (88.3% vs 27.3%), p < 0.0001 3.3.2.5 Survival according to the T-class of the primary tumor Survival rate for years with T2 and T3 ratings was higher than that of T4 patients (90% and 80.6% vs 20.9%), p < 0.0001 3.3.2.6 Survival by histopathological classification Survival rate for years with shallow spreading and larva migrans was higher than that of parietal and localized moles (62.2% and 57.4% vs 15% and 5.7%), p < 0.0001 3.3.2.7 Survival by number of regional metastases Survival for years in patients with no regional lymph node metastasis was higher than in patients with metastatic node, to metastatic nodes and or more metastatic nodes (88.3% vs 33.8%, 10.9%, and 11.5%, respectively), p < 0.0001 3.3.2.8 Survival according to Clark classification Survival rate for years in Clark II-III was higher than in Clark IV-V (85.3% vs 44.5%), p < 0.0001 3.3.2.9 Survival according to tumor microscopic ulcer Survival rate for years without microscopic ulcer was higher than with microscopic ulcer (76.3% vs 29.0%), p < 0.0001 3.3.2.10 Survival according to tumor multiplication ratio Survival for years has a higher divisor ratio < 1/mm2 than that of 16/mm2 and especially a divisor ratio > 6/mm2 (95.5% vs 3% and 5.9%), p < 0.0001 3.3.2.11 Survival by development stage Survival rate for years in radiating stage was higher than in vertical stage (87.2% vs 40.5%), p < 0.0001 3.3.2.12 Survival according to the degree of tumor-infiltrating lymphocytes Survival rates for years were higher at the level of dense tumorinfiltrating lymphocytes than in sparse tumor-infiltrating lymphocytes and no tumor-infiltrating lymphocytes (91.3% versus 59.1% and 13.0%), p < 0.0001 3.3.2.13 Survival according to vascular invasion tumor 15 Survival rate for years without vascular invasion was higher than with vascular invasion (69.4% vs 0.0%), p < 0.0001 3.3.2.14 Survival according to the micro satellites around Survival rate for years without microsatellites is higher than with satellites (70.5% vs 21.3%), p < 0.0001 3.3.2.15 Analysis of factors related to survival by Cox regression model There are two independent prognostic factors with statistical significance, p < 0.05, which are microscopic ulcer factor and vascular invasion factor Chapter DISCUSSION 4.1 GENERAL CHARACTERISTICS OF MELANOMA IN THE STUDY GROUP OF PATIENTS 4.1.1 Demographic characteristics of the study subjects 4.1.1.1 Distribution of age 4.1.1.2 Distribution of sex 4.1.1.3 Distribution of occupations 4.1.1.4 Distribution of family history 4.1.2 Clinical characteristics of melanoma 4.1.2.1 Time of illness 4.1.2.2 First detected symptoms 4.1.2.3 Tumor location 4.1.2.4 The skin appears to have a tumor, and there is a sharp pain in the skin 4.1.2.5 Tumor morphology 4.1.2.6 Tumor color 4.1.3 Histopathological characteristics of melanoma 4.1.3.1 Histopathological forms 4.1.3.2 Microfield Divisor Ratio 4.1.3.3 Clark's invasion of tumor 4.1.3.4 Development stage of tumor 4.1.3.5 Microsatellite nucleus around tumor 4.1.3.6 Microscopic tumor ulcer 4.1.3.7 Lymphocytes infiltrate the tumor at the stage of vertical growth 4.1.3.8 Tumor invades vessels 4.1.3.9 Primary tumor thickness grading (pT) 4.1.3.110 Classification of regional lymph node metastasis (pN) 4.1.3.11 Classification of disease stage 16 4.2 CHARACTERISTICS OF REGIONAL LYMPH NODE METASTASIS IN MELANOMA IN THE STUDY GROUP OF PATIENTS 4.2.1 Association of disease duration with regional lymph node metastases The group with disease duration < months had the regional metastasis rate of 21.1%; group with disease duration ≥ months had regional lymph node metastasis rate of 83.1%, p = 0.002 In the study of Rajaee A et al (2021), the group with disease duration ≥ months had a higher rate of lymph node metastasis than the group with disease duration < months, respectively 43.2% compared with 12.6%, p divisors/mm2, regional lymph node metastasis rate 78.6% 4.2.10 Association of tumor ulcer factor with regional lymph node metastasis The rate of regional lymph node metastasis was higher in the group with microscopic ulcer than in the group without microscopic ulcer (84.6% vs 14.2%), p < 0.0001 Grande et al found the rate of regional lymph node metastasis in the group with tumor ulcer and the group without tumor ulcer was 68.0% and 15.7%, respectively, with p