Abstract of thesis: Research on clinical, subclinical characteristics and treatment results of lacrimal gland tumours

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Description of clinical and subclinical characteristics of lacrimal gland tumors at the National Institute of Ophthalmology. 2. Evaluation of treatment results of lacrimal gland tumors of the study group of patients. 3.Analysis of some factors related to the results of treatment of lacrimal gland tumors.

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Nội dung Text: Abstract of thesis: Research on clinical, subclinical characteristics and treatment results of lacrimal gland tumours

MINISTRY OF EDUCATION MINISTRY OF HEALTH AND TRAINING HANOI MEDICAL UNIVERSITY HA THI THU HA RESEARCH ON CLINICAL, SUBCLINICAL CHARACTERISTICS AND TREATMENT RESULTS OF LACRIMAL GLAND TUMOURS Specialism: Ophthalmology Code: 62720157 ABSTRACT OF THESIS HÀ NỘI - 2022
The thesis has been completed at HANOI MEDICAL UNIVERSITY Supervisors: Supervisor1: A.Prof. Pham Trong Van Supervisor 2: PhD. Nguyen Quoc Anh Reviewer 1: Reviewer 2: Reviewer 3: The thesis will be present in front of board of university examiner and reviewer lever at on 2022 The thesis can be found at: National Library National Medical Informatics Library Library of Hanoi Medical University
THE LIST OF WORKS HAS PUBLISHED AND RELATED TO THE THESIS 1. Ha Thi Thu Ha, Nguyen Thi Thanh Huong, Nguyen Quoc Anh, Pham Trong Van (2020). “Clinical features and computed tomography of lacrimal gland tumors”. Journal of Vietnamese Medicine, issues 1&2 in 2020, pp. 173 - 176. 2. Ha Thi Thu Ha, Nguyen Quoc Anh, Nguyen Ngoc Mai, Tran Hong Nhung, Pham Trong Van (2020). “Correlation between clinical features, computed tomography images and histology of lacrimal gland tumors”. Journal of Practical Medicine, 2nd issue, 2020, pp. 12 - 15. 3. Ha Thi Thu Ha, Nguyen Thi Thanh Huong, Nguyen Quoc Anh, Pham Trong Van (2021). “Results of treatment of lacrimal gland tumors”. Journal of Vietnamese Medicine, No. 1, 2021, pages 149 - 154.
1 INTRODUCTION A lacrimal gland tumor is a polymorphic lesion with characteristic clinical features, pathology and therapeutic results. Classification of lacrimal adenomas is based on the World Health Organization (WHO) 1991 classification of salivary gland tumors. Lacrimal adenomas account for 3% to 18% of orbital tumors. Tumors are divided into two groups: epithelial (20- 45%) and non-epithelial (55-80%). The lacrimal adenocarcinoma consists of 55% of the benign (the most common mixed lacrimal gland tumor) and 45% of malignant (the most common and the most adenoid cystic carcinoma, accounting for 66% of the malignancies). Lacrimal gland cancer is the one with high malignancy, especially adenoid cystic carcinoma with high local recurrence and distant metastases, usually poor therapeutic result, with a mortality rate of about 50%. The lacrimal non-epithelial neoplasms are mainly lymphoid lesions including benign lymphoid hyperplasia, atypical lymphoid hyperplasia, and malignant lymphoma. In Vietnam, there are no report on the incidence of lacrimal gland tumors. Early detection and diagnosis of malignant lacrimal adenomas are relevant for the monitoring, management, prognosis and survival rates of patients. Diagnosis is based on clinical features, computed tomography images and pathology. And, clinical features and oriented computed tomography diagnosis and pathology have definite diagnostic value. In recent years, the understanding of the pathogenesis of lacrimal gland tumors has been improved, treatment method brings about better results. Treatment of benign epithelial tumors is surgical resection of the entire tumor. In contrast, the treatment of lacrimal adenocarcinoma remains controversial. Eye-sparing and radiation therapy combined with chemotherapy are the main trends in the treatment of lacrimal carcinoma. Targeted therapy studies aimed at oncogenes will have been used in the treatment of adenoid cystic carcinoma, particularly of value in recurrent or metastatic cancer. Treatment of lymphoma includes monitoring, systemic corticosteroids, local radiation therapy, or chemotherapy. In Vietnam, the actual rate of cancer, including orbital cancer in general and lacrimal gland cancer in particular, is increasingly reported. At the National Institute of Ophthalmology, many patients with lacrimal gland cancer come for examination and treatment at a metastatic stage. Therefore, the treatment results are very poor, even death within a short time since the disease is detected. Lacrimal gland tumors are very diverse in clinical morphology, the diagnosis of lacrimal gland tumor type, benign and malignant nature of the tumor and treatment prognosis are still challenging for clinicians. Up to date, the studies on lacrimal gland tumors in Vietnam are still incomplete and the systematic and limited treatment methods have not caught up with the world trend. We conducted the thesis "Research on clinical, subclinical characteristics and treatment results of lacrimal gland tumors" with three objectives: 1. Description of clinical and subclinical characteristics of lacrimal gland tumors at the National Institute of Ophthalmology. 2. Evaluation of treatment results of lacrimal gland tumors of the study group of patients. 3. Analysis of some factors related to the results of treatment of lacrimal gland tumors.
2 THE SCIENTIFIC AND PRACTICAL CONTRIBUTION OF THESIS For the first time in Vietnam, there is a summary study on a large number of patients with lacrimal gland tumors. Describe the clinical and paraclinical features of two types of lacrimal gland tumors, namely epithelial and non-epithelial neoplasms (mainly lymphoid lesions), showing the relationship between clinical and subclinical signs. Evaluate the results of treatment methods for each different type of lacrimal gland tumor and analyze the factors affecting the treatment outcome of each method. Based on research, ophthalmologists have more knowledge in the diagnosis, treatment indications and prognosis with different types of lacrimal gland tumors. STRUCTURE OF THE THESIS The thesis is presented 156 pages: Introduction 2 pages, Overview 33 pages, Meth odology 20 pages, Results 49 pages, Discussion 46 pages, Conclusion 2 pages, Contribution of Thesis 1 page, The direction of further research of the thesis 1 page, Recommendation 1 page with 175 Vietnamese and English references. CHAPTER 1: OVERVIEW 1.1. Clinical and paraclinical features of lacrimal gland tumors 1.1.1. Outline of lacrima gland 1.1.2. Classification of lacrimal gland tumors based on histopathology The four most common types of lacrimal adenomas are benign lacrimal gland mixed tumor, lacrimal gland carcinoma, lymphoid hyperplasia and malignant lymphoma. 1.1.3. Clinical and subclinical characteristics of some common lacrimal gland tumors * Benign lacrimal gland mixed tumor Mixed lacrimal gland tumor is the most common epithelial tumor of the lacrimal gland, accounting for 10-20% of lacrimal gland lesions and 1% of orbital tumors, usually originating from the orbital lobe, sometimes from the eyelid lobe (10%). The tumor usually grows slowly, without pain, the first sign is facial disproportion, ocular deviation, with limited ocular movement or diplopia. On computed tomography, the tumor usually presents as a round or oval mass, smooth, well-demarcated, smooth shell, ocular displacement or deformity, mild to moderate attenuation. Histopathology is often cortical, clearly demarcated, characterized by epithelial and parenchymal proliferation that varies according to tumor morphologies. * Lacrimal gland carcinoma Lacrimal gland carcinoma includes adenoid cystic carcinoma, carcinoma ex pleomorphic adenom, adenocarcinoma... Adenoid cystic carcinoma is the second most common form of epithelial lacrimal gland tumour and is the most common malignant carcinoma of the lacrimal gland, accounting for about 1.6% of orbital tumors and 3.8% of primary orbital tumors. The disease occurs in both sexes. The average age of patients is about 40 (6.5 - 79 years old). Clinical features include pain, eyeball displacement, eyelid swelling, and eyelid numbness. Computed tomography showed a spherical, round, or elongated tumor, running along the outer orbital wall, dilated lacrimal fossa with bony infiltrates, serrated margins, and irregular density. On the bony window there may be tumor infiltrates into the dura mater and intracranially. In terms of histopathology, the gross tumor size can be small or large, the density is firm, often multi-size, the limit is unknown, the face is rough and invasive.The tumour-section is
3 gray-white. Necrosis and bleeding are rare, usually present only in cancers with high histology. Microscopically, adenoid cystic carcinoma has many different morphologies: sieving, fibrous, basal (solid), cystic, and tubular. It is most common to have a mixture of two or more of these morphologies in the same tumor, in different regions. The staging of lacrimal gland cancer is based on the TNM classification system proposed by Denoix in 1943, which divides the cancer stage based on three factors: tumor (Tumor), lymph node (Node) and metastasis (Metastasis). * Lymphoid hyperplasia Lymphoid lesions include benign lymphoid hyperplasia, atypical lymphoid hyperplasia, and malignant lymphoma. Lymphocytic hyperplasia is characterized by insidious onset, progressive swelling of the eyelids causing bulging or drooping of the eyelids, painless, common in the elderly, often bilateral, may have signs of inflammation, and a palpable mass in the upper outer corner of the eye socket. On computed tomography, the lymphoid organization surrounds the lacrimal fossa, clearly demarcated, oblong, closes to the wall of the eyeball, clearly enhanced with contrast, rarely bone lesions. Histopathology is characterized by dense infiltrate of small lymphocytes, the formation of reactive lymphoid follicles of different sizes reminiscent of a normal lymph node structure with multiple nuclei in the nucleus accumbens. * Lymphoma Malignant lymphoma is a proliferative non-Hodgkin's low-grade B-lymphocyte, common in the elderly. Tumor is most common in the 70-80 year old age group. Manifestations of the disease in the lacrimal gland can be unilateral or bilateral, the rate of bilateral tumors accounts for 25%. Duration of disease onset is usually less than 1 year. Malignant lymphoma often has chronic symptoms, slowly protruding eyes, drooping eyelids, palpable mass in the upper outer orbit, firm rubbery mass, painless. On computed tomography, the tumor is ovoid or oblong, cast around the orbital structure, with moderate contrast enhancement, usually without bone lesions, rarely with calcification. The histology of extranodal marginal zone lymphoma is characterized by a dense infiltrate of small cells with broad cytoplasm, slightly notched nuclei, and absence of nuclei like marginal cells. 1.2. Management of lacrimal gland tumour Lacrimal adenomas are very variable in appearance and have many treatment options, depending on the specific case. 1.2.1. Treatment of benign mixed lacrimal gland tumor Treatment of benign mixed lacrimal gland tumor is mainly complete resection of the tumor, removal of the entire tumor envelope, and no biopsy to avoid tumor recurrence. 1.2.2. Treatment of lacrimal gland carcinoma Treatment includes surgery combined with radiotherapy and chemotherapy. Prognosis is often poor. The goals of treatment of lacrimal carcinoma are local control and prevention of distant metastases. The issue of appropriate local treatment for lacrimal carcinoma is controversial. The guideline of eye-sparing surgery combined with radiation therapy allows local control, preserves vision and less damage to the ocular surface. Intra-arterial chemotherapy or adjuvant intravenous chemotherapy to reduce tumor size is very effective in combination with eye-sparing surgery, but the longevity benefit of adjuvant chemotherapy has not been demonstrated. Preoperative adjuvant intra-arterial chemotherapy is only applicable to patients with intact lacrimal artery. Targeted therapy is the cancer
4 gene applied to cases of metastatic or recurrent cancer. 1.2.3. Treatment of lymphoid hyperplasia Treatment of lymphoma is based on histopathological results, depending on each specific case. Benign lymphoid hyperplasia is treated initially with high-dose steroids and/or external beam radiation therapy with approximately 20Gy. Rituximab (monoclonal antibody) is also an optimal choice in cases that do not respond to radiation therapy. 1.2.4. Treatment of malignant lymphoma Treatment of malignant lymphoma in local radiation therapy, chemotherapy in patients with systemic lymphoma. The immunological approach, using interferon-α for malignant lacrimal lymphoma, is not yet officially recognized. The currently recognized monoclonal antibody used for malignant lymphomas, especially low-grade B-cell lymphoma, is the anti-CD20 rituximab monoclonal antibody that destroys B cells. 1.3. Factors associated with treatment outcome Factors that may affect treatment outcomes include: - Age: Tellado et al (1997) reported that younger patients with cystic adenocarcinoma had a better prognosis than older patients. - Tumor size: Based on the tumor size, it is possible to choose the appropriate treatment method (surgery or medical treatment), choose the surgical method (partial or complete tumor removal). Tumor size is also related to tumor status after treatment, ocular deviation, ocular movement limitation, double vision, convexity, side effects of treatment (complications), tumor recurrence, and death. - Tumor location: determine the appropriate approach to the tumor. - Pathological properties of the tumor: including benign or malignant nature and AJCC grade affect treatment methods, tumor recurrence rate and mortality rate. - Treatment methods: affect post-treatment complications, tumor recurrence, and death. - The status of surrounding infiltrates: affects the choice of treatment method, tumor recurrence and mortality rate. Ford et al (2021) showed a statistically significant association between nerve infiltration and high local recurrence rates in patients with lacrimal carcinoma. 1.4. Research situation in Vietnam Hoang Cuong (2015) describes clinical and subclinical characteristics of ocular adnexal lymphoproliferative diseases and comments on treatment results of ocular adnexal lymphoproliferative diseases. Tran Thi Thu Hang (2018) describes clinical and subclinical characteristics of eye protrusion due to orbital tumor at the National Institute of Opthalmology and learns some factors related to pathology - clinical and near-sightedness clinical manifestations of some types of orbital tumors. Doan Minh Hoang (2018) specifically mentions conjunctival lymphoma, describes the clinical and subclinical characteristics of conjunctival lymphoid proliferation and evaluates the results of treatment for conjunctival lymphoma. Mai Trong Khoa et al (2020) reported "Treatment of a rare case of lacrimal gland cancer at the Nuclear Medicine and Oncology Center, Bach Mai Hospital" is a clinical case of carcinoma. Rare primary glandular tissue derived from lacrimal gland has been successfully treated. However, to date, there have been no published studies on the clinical, laboratory and treatment results of general lacrimal adenomas and different types of lacrimal gland tumors.
5 CHAPTER 2 PATIENTS AND METHODS 2.1. Patients The patient who came for examination and treatment of lacrimal gland tumor at the National Institute of ophthalmology from October 2016 to December 2019. Selection of patients with a confirmed diagnosis based on pathological results of the following 4 groups of lacrimal gland tumors: benign mixed lacrimal gland tumor, lacrimal gland carcinoma, benign lymphoid hyperplasia, malignant lymphoma. 2.2. Methods 2.2.1. Design Prospective descriptive study 2.2.2. Study sample size Apply the formula to calculate sample size: n: study sample size z: confidence limit value. Choose reliability as 95% → = 1.96 α: Statistical significance level, α = 0.05 p: recurrence rate of lacrimal gland tumor (choose p = 0.22) : 0.36 (relative value from 0.1 → 0.4) Qua tính toán n = 105.09 Through calculation n = 105.09 How to choose a research sample: From October 2016 all eligible lacrimal adenomas patients were randomized, continuously until the sample size needed for the study was reached. We collected 108 patients. 2.2.3. Variables and how to evaluate variables according to research objectives *Clinical and subclinical characteristics - Age: mean age (quantitative), age group (qualitative) divided into 5 age groups: 0 - 20, 21 - 40, 41 - 60, 61 - 80, 80+ - Gender (qualitative): Male / female - Reason for admission (qualitative) - Time from illness to medical examination: Mean time (qualitative) and time group (quantitative) divided into 3 groups: ≤ 6 months, 7 - 12 months, > 12 months - How to assess visual acuity: Visual acuity according to WHO classification of visual acuity: ≥ 20/25 : Normal
6 - How to assess ophthalmic restriction: Ocular restriction is divided into levels according to the VISA classification of Dolman (2006): 0º to < 15º: Severe restriction 15º to < 30º: Moderate Limit 30º to < 45º: Slight limitation > 45: Unlimited - How to evaluate double vision: yes or no - How to evaluate convexity: protrusion ≥ 12mm or protrusion difference 2 mm. - How to evaluate tumor characteristics: Tumor location, size, shape, border, boundary, density, calcification image in the tumor, pressure on the eyeball, pressure on the eye muscles, degeneration in the tumor, surrounding infiltration, changes in bone structure. - How to evaluate histopathology: macroscopic, microscopic, H & E staining results, immunohistochemistry results - Diagnosis: histopathological characteristics (benign, malignant), AJCC staging for malignant lacrimal adenomas, whole-body lymphoma testing, PET-CT scan. *Treatment results - Methods: Removal of the entire tumor (including the shell), partial removal of the tumor - preserving the eyeball, removing the orbital bone, dredge the orbital organization - Tumor approach: The line through the upper eyelid crease without bone opening, the line through the upper eyelid crease with bone opening, the line below the eyebrow arch, the conjunctival line and the upper map - Evaluation in surgery: Old surgical scar, tumor access status, surrounding tissue adhesion status, tumor removal status (partial, total tumor), tumor characteristics during surgery (size, shape, part of damaged tear gland is lobe or eye socket) - Follow up treatment at the time: 1 week, 1 month, 3 months, 6 months, 1 year Monitor visual acuity, intraocular pressure, eyeball displacement, ocular movement, diplopia, protrusion, assessment of tumor on clinical examination: remaining tumor/recurrence, tumor cessation, complications after treatment, metastasis, tumor recurrence and death. *Factors related to treatment outcome - Tumor size with treatment results - Tumor location with treatment results - Infiltrates around with treatment results - Anatomical characteristics and treatment results - Treatment methods with treatment results 2.2.4. Research tools and means 2.2.5. The method of data collection 2.2.6. Research process * Ask about illness * Clinical examination * Computed tomography * Take samples by biopsy or surgical removal of the tumor * Pathological examination * Definitive diagnosis, selection of research patients * Treatment: Surgery to remove the tumor, radiation therapy, chemotherapy,
7 corticosteroids *Monitor the results after treatment: at 1 week, 1 month, 3 months, 6 months and 12 months. * Evaluation of treatment results Evaluation of treatment methods, surgical methods, clinical features: eyeball displacement, ocular movement, diplopia, protrusion, tumor status (still or no tumor) , complications after treatment, recurrence, metastasis, death. - Criteria to evaluate treatment results based on the following factors: + Restriction of transportation (yes, no) + Dual vision (yes, no) + Tumor status after treatment (still tumor, no tumor) + Evaluation of eyeball displacement (mm) + Eye protrusion (mm) Comparison of the above factors at the time points before treatment and after treatment 1 week, 1 month, 3 months, 6 months and 1 year. + Complications after treatment (yes, no) + Recurrence + Metastasis + Mortality: analysis of Kaplan-Meier chart of malignant lacrimal tumor mortality during follow-up - Find factors related to treatment results based on analysis of the relationship of input variables (independent variables) such as tumor location, tumor size, surrounding tumor infiltration, anatomical characteristics Diseases, treatment methods and output factors (dependent variables) are treatment outcomes including: complications after treatment, tumor recurrence or death. Related factors and treatment results also refer to and are based on the latest research on the treatment of lacrimal gland tumors such as Ford (2020), Claros (2019), Ahn (2019)… * Completing the research case * The role of the PhD student: is the person who directly inquires about the disease, performs clinical examination, assigns subclinical instructions, consults the patient before treatment, directly conducts biopsies, performs surgery or participates in the surgical team, directly continue medical treatment or collect treatment information at other treatment facilities, directly collect patient data at the time of re-examination, process and analyze data. 2.3. Data processing and analysis Analysis on SPSS 22.0 software. Use descriptive statistics algorithms. Research errors include sampling error (random or non-random) and information error. The solution is to choose a large enough sample size and collect complete and accurate patient information. 2.4. Research ethics The patient consented to participate in the study and to use personal photos in the study. All pre-treatment agreements are signed in writing by the patient. The study was conducted with the consent of the Board of Directors of the Central Eye Hospital and approved the outline review committee of Hanoi Medical University.
8 CHAPTER 3 RESULTS 3.1. Clinical and paraclinical features of lacrimal gland tumors We examined and treated 108 lacrimal gland tumors, followed up for an average of 30.7 ± 12.46 months (0.25 - 50 months). The research results are presented as follows: 3.1.1. Characteristics of patients with lacrimal gland tumor * Age: The mean age of lacrimal gland tumor is 52.9 ± 15.3 (7 – 96 years old). The most common age group is 41-60 years old. * Gender: Female predominates in the group of mixed benign lacrimal gland tumor and lymphoid hyperplasia, male predominates in the group of carcinoma and malignant lymphoma. 3.1.2. Clinical characteristics of patients with lacrimal gland tumor * Characteristics according to the diseased eye In 108 patients with lacrimal adenoma, 36.1% of patients had bilateral and 63.9% of patients with unilateral (35.2% left eye and 28.7% right eye). The group of mixed benign lacrimal gland tumors and carcinomas only had one eye, there were no cases with both eyes. In the group of lymphoid hyperplasia and malignant lymphoma, the proportion of patients with binocular disease was 61.7% and 35.7%, respectively. * Reason for medical examination The most common reasons for examination were palpable mass and protrusion of the eye. Pain was the most common in the carcinoma group, accounting for 68.7%. There are also other reasons such as watery eyes, swollen eyelids, drooping eyelids, eyelid numbness, blurred vision and double vision. * Time from onset of symptoms to medical examination The average time from symptom onset to clinical examination of lacrimal gland tumors was 14.43 months (1 - 84 months). In particular, the lacrimal adenocarcinoma group had the shortest disease duration, an average of 7.88 months. The group of mixed benign lacrimal gland tumor and lymphoid hyperplasia had symptom onset time >12 months, respectively 47.1% and 25.5%. The group of lacrimal adenocarcinoma and malignant lymphoma had symptom onset time ≤ 6 months, respectively 62.5% and 39.3%. * Relevant medical history With common lacrimal gland tumor, the majority did not have systemic changes (95.4%), only 4.6% had systemic changes such as lymph nodes in the neck, groin, and armpits. * Characteristics of clinical examination - Maximum corrected visual acuity The group of mixed benign lacrimal gland tumors accounted for 58.8%, and there were no patients with severe visual impairment. The lacrimal carcinoma group had 33.3% severe vision loss. The malignant lymphoma group had 2.4% severe visual impairment. The malignant lymphoma group had 7.4% severe visual impairment. - Intraocular pressure Patients in the lacrimal gland tumor groups did not have glaucoma. - Physical symptoms The most common physical symptoms are palpable upper-outside tumor, eye
9 protrusion, eyelid deformity, S-shape, and eyelid swelling. There are also other signs such as misalignment of the eyeball, limited eye movement or double vision. - Average protrusion The mean convexity of lacrimal adenomas is 15 ± 3.9 mm (10 – 23mm). A difference of about 2 - 4 mm occurred between the lacrimal adenocarcinoma group and the lymphoma group. Lymphoid hyperplasia does not cause significant protrusion. 3.1.3. Paraclinical features of lacrimal gland tumors * Features of computed tomography images of lacrimal adenomas - Tumour size The average size of lacrimal gland tumor on computed tomography is 31 ± 11 (10 – 76 mm). - Tumour location Tumor location is mainly in the upper and outer position. - Tumor characteristics The shape of the lacrimal gland tumor is mainly oval, the tumor border is mainly regular, the tumor border is mainly clear in the group of lymphoid hyperplasia 94.9% and mixed benign lacrimal gland tumor 92.9%. The proportion of heterogeneous tumors seen in mixed benign lacrimal gland tumor, carcinoma, and malignant lymphoma was 57.1%, 93.7%, 53.6%, respectively, homogeneous tumors seen in lymphoid hyperplasia was 89.7%. The phenomenon of calcification only seen in carcinoma is 18.8%. Intratumoral degeneration occurred in benign mixed lacrimal gland tumor with the rate of 7.1% and carcinoma in 6.3%. - Influence of tumor on surrounding structures Eyeball pressure is common in epithelial tumors, mixed benign lacrimal gland tumors account for 71.4%, and carcinoma accounts for 62.5%. Pressure on the oculomotor muscle was the most common in carcinoma, accounting for 31.3%. Surrounding infiltrates were only seen in lacrimal carcinoma and malignant lymphoma in 46.7% and 10.7%, respectively. Changes in bone structure seen in mixed benign lacrimal gland tumor and carcinoma were 28.6% and 50%, respectively. - Changes in bone structure Structural changes include bone erosion, bone compression, bone thickening, pitting, and bone defect. Bone erosion was found in mixed benign lacrimal gland tumor and lacrimal carcinoma at 28.6% and 68.8%, respectively. Common bone changes in lacrimal carcinoma include bone compression (6.3%), bone thickening (37.5%), pitting (31.3%), and bone defect (6.3%). * Histopathology characteristics - Macroscopically, the benign mixed lacrimal gland tumor was mainly resected with the whole mass including the capsule (88.2%), lacrimal carcinoma 50% ruptured. Lymphoid lesions were mainly partially resected for diagnostic histopathology (lymphocyte hyperplasia 85.1%, malignant lymphoma 96.4%). In terms of microscopy, most of the groups had tumor resection, the rate in the group of mixed benign lacrimal gland tumors, lacrimal carcinoma, lymphoid hyperplasia and malignant lymphoma was 76.5%, respectively. 87.5%, 95.7%, 100%. - Characteristics of distribution of lacrimal gland tumors according to H&E. staining results
10 In 108 patients with lacrimal adenoma, there were 33 patients with epithelial tumors (30.5%) and 75 patients with non-epithelial tumors (69.5%). Lacrimal adenocarcinomas include mixed benign lacrimal gland tumors accounting for 15.7% and lacrimal carcinoma accounting for 14.9%. Lymphoma including lymphoid hyperplasia accounts for 43.5% and malignant lymphoma or malignant lymphoma accounts for 25.9%. - Percentage of patients undergoing immunohistochemistry Immunohistochemistry was mainly done for the group of patients with lymphoma including 19.1% of patients with lymphoid hyperplasia and 89.3% of patients with malignant lymphoma. - Distribution of types of lymphoid lesions based on immunohistochemistry Among 75 lymphoma patients, there were 47 lymphoma cases (including 74.5% benign lymphoma and 24.5% atypical lymphoma) and 28 cases of malignant lymphoma (18 malignant lymphomas). Extra nodal margin (EMZL), 1 mantle cell lymphoma, and 9 small lymphocytic lymphoma). - Microscopic characteristics of the group of malignant lacrimal adenomas + Distribution of adenoid cystic carcinoma types Of the 16 cases of lacrimal carcinoma, 12 were adenoid cystic carcinoma which was the most common form of lacrimal carcinoma. Among them, there are 7/12 (58.3%) sieves, 4/12 (33.3%) tubes and 1/12 (8.3%) mixed types (including sieves and tubes per sample). + Distribution of microscopic infiltrates in the group of malignant lacrimal adenomas Bone infiltrate was found in carcinoma 37.5%, vascular infiltration was found in carcinoma 6.3%, nerve infiltration was seen in both carcinoma and malignant lymphoma, the ratio is 12.5% and 3.6%, respectively, muscle infiltration was found in both carcinoma and malignant lymphoma with the rates of 25% and 7.1%, respectively. + Pathological characteristics according to AJCC stage of lacrimal gland cancer The AJCC grading of lacrimal gland malignancies including lacrimal carcinoma and malignant lymphoma showed that the tumor was predominantly at T2, N0, and M0 stages. 3.1.4. The relationship between clinical features, computed tomography features and histopathology of lacrimal adenomas * Relationship between clinical features and computed tomography of lacrimal adenomas * The relationship between pathological and clinical features * Relationship between pathological characteristics and computed tomography 3.1.5. Diagnose * Appropriateness of diagnosis according to computed tomography and pathological diagnosis The diagnostic concordance between computed tomography and histopathology in the mixed benign lacrimal gland tumor was 35.3%, in the lacrimal carcinoma group was 50%, in the lymphoid hyperplasia group was 97.9 %, in the group of malignant lymphoma was 42.9%. * PET-CT scan A total of 33/108 (30.4%) patients with lacrimal adenomas were subjected to PET-
11 CT. None of the patients in the group of mixed benign lacrimal gland tumors underwent PET-CT. The main group of malignancies receiving PET-CT were 50% lacrimal adenocarcinoma, 85.7% malignant lymphoma. In the group of malignant lymphomas, PET-CT had 33.3% abnormal results, that is, there were systemic lesions (metastasis to lymph nodes, internal organs...). * Whole body lymphocyte test There were 57/75 patients with lymphoma who had a systemic lymphatic test to detect systemic lymphoma, in which the group of lymphoid hyperplasia had 68.1% and the group of malignant lymphoma had 89.3%. Among 57 lymphoma patients tested for systemic lymphocytosis, 3.2% of lymphoid hyperplasia was associated with disseminated lymph node involvement in the whole body (neck, axillary, inguinal), 16% of malignant lymphoma was associated with lesions in lung injury, tuberculosis, kidney. 3.2. Results of treatment of lacrimal gland tumor 3.2.1. Methods of treating lacrimal gland tumors Among 108 patients with lacrimal gland tumor, 4.6% dropped out of treatment right from the time of follow-up after 1 week, 19.4% had surgery alone, 18.5% had chemotherapy alone, 42.6% used corticosteroids alone and 13.9% in combination. In the group of benign mixed lacrimal gland tumors, 100% of patients had surgery. The group of lacrimal adenocarcinoma is mainly combination treatment, accounting for 68.8%. The group of lymphoid hyperplasia was mainly treated with corticosteroids (93.6%) and there was 1 patient using immunosuppressive methods in combination with corticosteroids. The group of malignant lymphomas was mainly treated with chemotherapy (71.4%). 3.2.2. Results of treatment of lacrimal epithelial tumor * Indications for surgery of lacrimal epithelial tumor Among 33 cases of lacrimal epithelial tumor, 93.9% had indications for surgery, 100% of patients with mixed benign lacrimal gland tumor were surgically removed. In 16 patients with carcinoma of the lacrimal gland, 87.5% had surgery to remove the tumor. * Surgical methods of lacrimal epithelial tumor Group of 100% benign mixed lacrimal gland tumors were resected the whole mass including the shell. The primary group of lacrimal adenocarcinomas is extensive tumor resection and eye-sparing. In addition, there is dredging of orbital organization, partial removal of tumor, these methods may or may not be combined with orbital bone resection. * The path to the eye socket approaches the lacrimal epithelial tumor The most commonly used approach to the epithelial tumor was the upper eyelid crease with osteotomy (35.5%) and the upper eyelid crease without osteotomy (25.8%). The group of mixed lacrimal gland tumors mainly used the upper eyelid fold line with bone opening (52.9%). The lacrimal adenocarcinoma group has a diverse tumor approach. * Evaluation in surgery The group of lacrimal adenocarcinoma has 2 patients without surgery. Among surgical patients, 50% of patients have old surgical scars. Most lacrimal
12 adenocarcinomas have easy access to the tumor (100% and 78.6%). In surgery, 100% of benign mixed lacrimal gland tumors did not have fibrous adhesions, whereas in lacrimal carcinoma, 92.9% had adhesions when removing the tumor. At the end of surgery, 100% of benign mixed lacrimal gland tumors removed the whole mass, 71.4% of lacrimal carcinomas were only partially removed. * Tumor characteristics in surgery The group of mixed benign lacrimal gland tumors and carcinomas both ranged in size from 2.1 to 4cm. The shape of the epithelial tumor is mainly oval (67.7%). The tumor surface in the group of benign mixed lacrimal gland tumors was mostly smooth, accounting for 94.1%, and the lacrimal carcinoma group was mainly rough, accounting for 85.7%. The tumor margin of the mixed group of benign lacrimal gland tumors is mainly made up of 100%, and the group of adenocarcinomas is mainly irregular margin, accounting for 85.7%. Both groups had a density of mainly solid tumors accounting for 94.1% and 100%, respectively. The tumor boundary in the group of mixed benign lacrimal gland tumors was mainly localized, accounting for 100%, and diffuse in the carcinoma group accounted for 92.9%. In terms of motility, lacrimal adenocarcinomas were mainly fixed tumors (71%), the fixed rate in the group of mixed benign lacrimal gland tumors and carcinoma accounted for 52.9% and 100%, respectively. . The rate of change in bone structure in the group of mixed benign lacrimal gland tumor and carcinoma was 23.5% and 42.9%, respectively. Both groups in lacrimal adenocarcinoma mostly changed lacrimal gland structure, especially lacrimal carcinoma group changed 100% of lacrimal gland structure. The structural changes of the lacrimal gland were mainly the orbital part, the benign lacrimal mixed tumor was 70.6%, and the lacrimal carcinoma was 92.3%. * Combination methods for the treatment of lacrimal carcinoma Of the 16 patients with lacrimal adenocarcinoma, 15/16 were treated and 1 patient was untreated. Among the treated patients, 26.7% had local tumor resection followed by additional radiation therapy, 20% had local tumor resection followed by additional chemotherapy, 13.3% had organ removal. orbit (with 1 patient combined with orbital osteotomy + 1 patient without orbital bone resection) followed by additional radiation therapy, 13.3% local excision followed by radiation therapy and additional chemotherapy, 13.3% were resected in situ alone, 6.7% exenteration followed by radiation therapy and additional chemotherapy, 6.7% exenteration alone. * Monitoring before and after surgery * Complications after treatment of lacrimal epithelial tumor The group of benign lacrimal gland tumors had eye complications including ptosis (94.1%), eyelid numbness (64.3%), eyelid scarring (52.9%), dry eye (48%). ) after surgery. This group did not have systemic complications after treatment. The group of lacrimal carcinoma after treatment had eye complications including: eyelid numbness (83.3%), eyelid drooping (70%), eyelid scar (13.3%), double vision (10). %) after surgery, dry eyes (62.5%), loss of eyelashes (60%), atrophy of tissues around the orbits (46.7%), redness and irritation of the skin around the orbits (20%) , corneal ulceration (10%), anterior chamber hemorrhage (6.7%), glaucoma (6.7%) after local radiotherapy. Systemic complications after medical treatment include nausea and
13 vomiting (40%), hair loss 40%, weight loss (26.7%), gastrointestinal disorders (20%), dredged eye socket (20). %), fever (13.3%). 3.2.3. Results of treatment for lymphoma of the lacrimal gland * Indications for surgery of lacrimal gland lymphoma In 75 patients with lacrimal gland lymphoma, 97.3% had no indication for surgery, only 2.7% had surgery. In 47 patients with lacrimal lymphoma, 95.7% had no indication for surgery. In 28 patients in the malignant lymphoma group, 100% did not have surgery. * Distribution of medical treatment methods for lymphoma In the group of lymphoid hyperplasia, 100% received corticosteroid therapy, 1 patient received immunotherapy, and no patient received chemotherapy or radiation therapy. Among 69 patients with malignant lymphoma treated, 82.6% received chemotherapy, 13% radiation therapy, and 4.3% received corticosteroids. * Monitoring before and after medical treatment * Complications after treatment for lacrimal gland lymphoma In the group of lymphoid hyperplasia, there was 1 patient with ptosis after surgery out of 2 patients who were operated on. Systemic complications in this group include digestive disorders (21.3%), weight gain (43.5%) after oral corticosteroids. The group of malignant lymphomas had complications with periorbital fat atrophy (23%), loss of eyelashes (23%), dry eyes (14.3%), redness and skin irritation (4.3 %) after radiation therapy. in place. Systemic complications after chemotherapy include: nausea and vomiting 65.2%, hair loss 87%, digestive disorders 65.2%, weight loss 65.2%, fever 4.3%, anemia 4 .3%, weight gain 4.3% 3.2.4. Tumour recurrence Mixed lacrimal gland tumor did not recur at all time points of 1 month, 3 months, 6 months, 1 year. The first recurrence of lacrimal adenocarcinoma was at 6 months (1 case), then there were 4 cases after 12 months. Recurrent lymphoid hyperplasia at all time points of 1 month, 3 months, 6 months, 1 year were 8.7%, 28.3%, 10.9%, and 6.5%, respectively. Malignant lymphoma recurred/tumor at 1 month 47.8%, then after 12 months, patients relapsed (8.7%). 3.2.5. Treatment results of the group of malignant lacrimal adenomas * Coordinated medical facilities to treat malignant lacrimal gland tumors Including: K hospital (58.2%), National Hospital of Hematology and Blood Transfusion (20.9%), Hanoi Medical University Hospital (9.3%), Nuclear Medicine and Oncology Center - Bach Mai Hospital (9.3%), Central Military Hospital 108 (2.3%). * Metastatic status of lacrimal gland cancer - Cancer of the lacrimal gland has 27.7% regional metastases and 27.7% distant metastases. - Malignant lacrimal adenoma had 11.1% lung metastasis, 5.6% liver metastasis, 5.6% lymph node metastasis and 5.6% brain metastasis. * Mortality and survival rates during follow-up - Among 44 patients with malignant lacrimal adenoma, 11.4% died, 88.6% survived or gave up. Mortality rates in patients with adenocarcinoma and malignant lymphoma were 25% and 3.6%, respectively. - The group of breast cancer of the lacrimal gland had an average survival time of 39.07 ± 3.76
14 months. The malignant lymphoma group had a median survival time of 48.68 ± 1.28 months. - The malignant lymphoma group had a longer mean survival time than the lacrimal carcinoma group. The difference in mean survival time between the two groups was statistically significant (p < 0.05) and shown in the chart below: Chart 3.1. Kaplan-Meier died of malignant lacrimal adenoma 3.3. Factors related to treatment outcome of lacrimal gland tumor 3.3.1. Relationship between tumor location and treatment results The rate of total tumor resection in the group where the tumor was located from the outer edge of the orbit to the back of the orbit was 17 times lower than in the group where the tumor was not located at this location. 3.3.2. Relationship between surrounding infiltrates and treatment results - There was a difference in the surgical rate in the infiltrative and non-infiltrative groups, this difference was statistically significant (p < 0.05). The rate of surgery in the infiltrative group was 4.71 times higher than in the non-infiltrative group. - The group with infiltrates had a 23.89 times higher risk of death than the non-infiltrated group. 3.3.3. The relationship between the anatomical characteristics of the tumor and the treatment results - The malignant group had a rate of surgery to completely remove the tumor 0.05 times lower than the benign group. - The malignant group has a 1.54 times higher risk of complications than the benign tumor group. 3.3.4. Relationship between treatment method and treatment outcome - The chemotherapy group had a 1.38 times higher risk of complications than the non- chemotherapy group. The group taking corticosteroids had a risk of complications 0.66 times lower than the group not using corticosteroids. - The surgical group had a 0.17 times lower risk of recurrence than the non-surgery group. - The radiotherapy group had a 0.2 times lower risk of recurrence than the non-radiotherapy group.
15 CHAPTER 4 DISCUSSION After examining and treating 108 patients with lacrimal gland tumors, followed-up for an average of 30.7 ± 12.46 months (0.25 - 50 months), we have the following discussions: 4.1. Clinical and paraclinical features of lacrimal gland tumors 4.1.1. Characteristics of patients with lacrimal gland tumor * Patient characteristics by age Our data and other authors show that the mixed benign lacrimal adenocarcinoma and lacrimal adenocarcinoma usually occur in the mean age around 40 years old, the lymphoma group has a higher mean age, especially malignant lymphoma usually in old age (mean age 69 years) * Patient characteristics by sex Our male/female ratio is similar to Yeşilta et al. (2018). Explaining the difference in the male/female ratio in the studies could be due to the different study sample sizes. 4.1.2. Clinical characteristics of patients with lacrimal gland tumor * Patient characteristics according to the diseased eye Our results and other authors agree that a special point to keep in mind when studying lacrimal gland lesions is that tumors can appear in both eyes. The special thing is that the epithelial tumor only appears in one eye, lymphoma can be unilateral or bilateral. * Reason for medical examination The main reasons are protrusion, palpable tumor, lacrimation, pain, double vision, drooping eyelids, eyelid swelling, eyelid numbness. This result is different from the study of Perez et al (2006), in 5 patients with mixed benign lacrimal gland tumor, there were 2 patients with drooping eyelids or protruding eyes (40%), 1 patient with pain (20%), 2 patients had limited eye movement (40%). Perez et al (2006) are patients with follicular adenocarcinoma who come to the clinic for various reasons: 10/12 (83.3%) swollen eyelids, 8/12 (66.7%) convexity eyes, 6/12 (50%) pain, 6/12 (50%) limited eye movement and vision loss, 1/12 (8.3%) facial paralysis. Yeşiltaş et al. (2018) are lymphoid hyperplasia with symptoms of eyelid swelling in 75%, ptosis in 25%, and palpable tumor 37.5%. * Time from symptom onset to medical examination The mean time of occurrence of the mixed benign lacrimal gland tumor group in our study group was 16.1 ± 12 (2 – 36 months). This result is longer than similar studies, this may be due to cognitive problems of our patients, patients do not recognize early, discreet symptoms until the disease manifests itself out and go to the doctor. * Clinical features - Visual acuty: In our study, the majority of lacrimal gland tumor patients had normal vision, accounting for 48%, only 8% had severe vision loss, similar to Demirci et al. (2008). The author summarizing on the group of lymphoma patients showed that the majority of patients' vision in the range of 20/20 - 20/40 was normal vision. The cause of vision loss is mainly due to senile cataract or anterior and posterior segment disease, not related to lymphoma. According to Perez et al. (2006), lymphoma rarely affects vision. If the vision is reduced, it may be due to nerve infiltration or compression of the optic nerve. In addition, vision loss may be due to central serous chorioretinopathy due to prolonged use of corticosteroids. - Physical symptoms: The most common physical symptoms of the study group were palpable tumors in the upper outer area, eye protrusion, S-shaped eyelids, eyelid
16 swelling. The tumor palpable sign accounted for 100% in the group of lacrimal adenocarcinoma and lymphoid hyperplasia, 75% in the carcinoma group and 64.7% in the group of mixed benign lacrimal gland tumors. The rate of protrusion was most common in the group of mixed benign lacrimal gland tumors (70.6%). Displacement of the eyeball is common in benign mixed lacrimal gland tumor (52.9%), followed by carcinoma (40%). S-shaped eyelids are common in malignant lymphoma group (28.6%). Eyelid swelling and eyeball compression are common in carcinoma, accounting for 43.8%. There are also other signs such as limited eye movement, double vision. This result is similar to the study of Claros et al (2019) on 52 patients with mixed benign lacrimal gland tumor, the most common protrusion, or accompanied by ocular displacement (off-axis protrusion). Thus, lacrimal adenomas are often palpable, and other clinical signs depend on the size, location and nature of the lesion. According to Liesegang et al. (1993), benign lymphoid hyperplasia is usually a solid mass in front of the orbit, rarely posteriorly. Malignant lacrimal lymphoma is usually a hard, firm mass, eyelid swelling, ocular displacement, and restriction of ocular movement. High- grade malignant lymphoma tends to be associated with anterior signs such as edema of the eyelids and conjunctiva, and protrusion of the eyes. Clinically, symptoms of tumor recurrence, bilateral orbital lesions, increased frontal symptoms such as eyelid swelling, eye protrusion... suggestive of malignant lymphoma. 4.1.3. Paraclinical features * Computed tomography image of lacrimal gland tumor Our results are similar to the study of Claros et al (2019) on 52 patients with mixed benign lacrimal gland tumor, computed tomography images show that most of the benign lacrimal glandular tumors have a homogeneous density (96.2%), well demarcated (94.2%), rarely calcified (3.8%). The rate of bone erosion was very low (5.8%), only 1 case had infiltrate surrounding tissues. In the group of lacrimal carcinoma, we and other authors found that the tumor location was mainly above, beyond and running behind the orbit. The average tumor size is 37 ± 18 mm, the tumor is mainly oval, elongated, has irregular margins, unclear boundaries, heterogeneous density, calcification in the tumor, pressure on the eyeball, ophthalmic muscle, degeneration in tumor, surrounding infiltrates, changes in bone structure (including bone erosion, bone compression, bone thickening, pitting, bone defect). Alkatan et al (2014) had 15/26 lacrimal adenocarcinoma patients underwent computed tomography, image of bone defect or erosion of the bone cavity was seen in 6/15 (40%) of patients, destruction. bone in 3/15 (20%) patients. The group of lymphoid lesions is usually molded around the globe with no bony lesions. In general, we and the authors have the same opinion about the characteristics of bone changes on computed tomography film. The contact of the tumor tissue and the bone, the direction of tumor growth in the vertical or horizontal direction, the tumor size, the time of tumor development are factors that determine the change of the bone. - About our lacrimal gland tumor in general, 29% of patients had the whole tumor resected with intact shell, most of them were ruptured or partially resected. In the group of benign mixed lacrimal gland tumors, 88.2% of the patients had the whole cortical mass removed, similar to the results of Alkatan et al (2014). Lymphoma resection in our study was mostly aimed at removing part of the tumor for pathology, so the gross histopathology rate with partial resection of the tumor accounted for the majority, lymphoid hyperplasia was 84, 8% and malignant lymphoma was 96.4%, characterized
17 by a salmon-colored mass, easily crushed. In terms of microscopy, we agree with some other authors that it is very important to analyze the microscopic pathology of follicular adenocarcinoma and evaluate the proportions of components with prognostic significance. - Results of H&E staining and immunohistochemistry Biopsy, H&E staining, and immunohistochemistry are essential and the gold standard for the diagnosis of lacrimal adenomas. It is important to clearly distinguish between benign and malignant lesions and benign lesions that turn malignant (after 5 years or more from the time of disease onset). In our study, lacrimal adenomas included 30.5% epithelial tumors and 69.5% non-epithelial neoplasms (mainly lymphomas), similar to the results of the above studies. Yeşiltaş et al. (2018) also showed that non- lacrimal adenocarcinomas were more predominant and that the rate of benign lacrimal mixed tumors was equal to the rate of lacrimal adenocarcinoma. - Distribution of follicular adenocarcinoma type based on immunohistochemistry We have 12/16 patients with follicular adenocarcinoma among lacrimal adenocarcinomas, accounting for the highest percentage. Among follicular adenocarcinomas, 7/12 (58.3%) were sieving, 4/12 (33.3%) were tubular, and 1/12 (8.4%) were mixed. This result is similar to the study of Desai et al (2019) with sieve form accounting for 42.9%, tubular form finding 35.7%, fibrotic form occurring 21.4%, basal form occurring 14.3%, combination of two or more forms (mixed form) accounts for 50%. Our study and other authors have the same result that squamous cystic adenocarcinoma is the most common. - Distribution of microscopic infiltrates around the tumor The lacrimal carcinoma infiltrated many tissues including bone (37.5%), vascular (6.3%), nerve (12.5%) and muscle (25%). Malignant lymphoma group had a lower rate of surrounding infiltration including nerve (3.6%), muscle (7.1%). This result is similar to the study of Ahmad et al (2009). Of the 7 patients with stage T2 follicular adenocarcinoma, 2/7 (29%) had evidence of neurological infiltration. Of the 15 patients with stage < T3 follicular adenocarcinoma, 6/15 (40%) had evidence of bone infiltration. Of the 38 patients with stage ≥ T3 follicular adenocarcinoma, 32/38 (84%) had evidence of bone infiltration. - Distribution of lymphoma types based on immunohistochemistry Lymphoma includes lymphoid hyperplasia (including benign lymphoproliferative, atypical lymphoma, and malignant lymphoma). In our study, there were 74.5% benign hyperplasia and 25.5% atypical hyperplasia. The group of malignant lymphomas is mainly malignant lymphoma in the extranodal margin, accounting for 64.3%. This result is similar to that of Rasmussen et al (2011) confirming the most common extranodal extranodal lymphoma. - AJCC staging of lacrimal gland cancer Staging of lacrimal adenocarcinoma is based on the AJCC staging of salivary gland malignancies combined with assessment of the yellow signs as clinical and pathological features. The results of our study on the AJCC grading of lacrimal glandular melanoma according to TNM staging based on a complete systemic assessment, as a result, showed that lacrimal adenocarcinoma was mainly at stage T2N0M0. The results of other authors are mainly tumor at T2 stage and there is no lymph node metastasis, distant metastasis, similar to our results.