A review of the expression of clinical, pathological and immunohistochemical features in 76 cases of thymoma – Tran Ngoc Dung

Journal of military pharmaco-medicine n o 1-2019 166 A REVIEW OF THE EXPRESSION OF CLINICAL, PATHOLOGICAL AND IMMUNOHISTOCHEMICAL FEATURES IN 76 CASES OF THYMOMA Tran Ngoc Dung1; Dinh Tien Truong1; Nguyen Khac Tuyen1 Nguyen Manh Hung1; Tran Viet Tien1 SUMMARY Introduction: Thymoma is the most common tumor in mediastinum. In Vietnam, there has not been any study regarding the pathological classification according to 2015 WHO classification, and the expression of imumunohistochemical markers of thymoma. Objectives: To determine these histological types of thymoma and expression of imumunohistochemical markers in thymoma according to 2015 WHO classification. Subjects and methods: 76 patients pathologically diagnosed with thymoma, underwent thymectomy at Department of Thoracic Surgery, 103 Military Hospital, from January 2010 to October 2018. Samples of thymoma were taken and performed H&E staining and imunohistochemical staining with these markers which were CD3, CD20, CD45, CD117, CKAE1/AE3, EMA, CK19, Ki67, p53. Results: A total of 76 patients, mean age 47.97 ± 13.43 and mean tumor size 4.09 ± 2.27 cm; patients with stage I disease were the most frequent (55.3%). 44.7% of patients had the invasive tumor. 59.21% of patients had accompanying myasthenia gravis, mostly at stage IIA (57.8%). The two most common types of thymic tumors were determined type B1 (26.3%) and B2 (26.3%). Conclusion: Generally, thymoma is rarely exposed on children. There was no difference between genders. The tumor size was quite large. Patients with stage I were the most frequent. The tumor could invade into the capsule. Type B1 and B2 thymoma were the most common. Myasthenia gravis could be found in patients with thymoma. Thymoma had a high mitotic count and poor expression of the mutation in tumor suppressor genes. * Keywords: Thymoma; Myasthenia gravis; Imumunohistochemical features. INTRODUCTION Thymomas are the most common tumors in the mediastinum, represent more than 45% in adults with mediastinal tumor. Patients at the age of 40 - 60 are more common, there is no sex predominance [4, 5]. According to American Cancer Society, the overall incidence of thymoma in the United State is about 0,15 per 100.000 person-years [6]. It is widely accepted that thymomas are malignant because of these invasive potentials. About 50% of patients with thymomas are asymptomatic, 30% of neoplasms manifest clinically by symptoms of myasthenia gravis (MG) [7]. Determining pathological subtypes of thymomas yield advantages in prognosis and treatment. In Vietnam, studies have been involved in clinical and radio-characteristics but not in pathological ones. This study was done with two goals: 1. 103 Military Hospital Corresponding author: Tran Ngoc Dung (bomongiaiphaubenh@gmail.com) Date received: 20/10/2018 Date accepted: 11/12/2018 Journal of military pharmaco-medicine n o 1-2019 167 - To evaluate the symptom of myasthenia gravis, pathological types of thymomas according to 2015 WHO classification. - To determine the expression of immunohistochemistry (IHC) markers in thymomas. SUBJECTS AND METHODS 1. Subjects. The study included 76 patients who had tumors in the anterior mediastinum, underwent thymectomy at Department of Thoracic Surgery, 103 Military Hospital; the tumors were subsequently pathologically diagnosed with thymomas, from January 2010 to October 2018 2. Methods. This is a retrospective and descriptive study, including: - Age, sex, Masaoka’s classification: Stage of thymoma, Osserman's classification: severity of clinical myasthenia gravis [8, 9]. - Pathological characteristics of the tumor: Size, pathological types according to 2015 WHO classification [10], the expression of immunohistochemistry markers CD3, CD20, CD45, CD117, CKAE1/AE3, EMA, CK19, Ki67, p53. (Ki67 is positive if there were more than 10% of tumor nuclei reacted) * Statistical analysis: Using SPSS 22.0 for Windows. RESULTS AND DISCUSSION 1. Clinical features. Table 1: Age and gender. Total Gender Age Male Female n % 20 - 29 5 4 9 11.8 30 - 39 5 5 10 13.2 40 - 49 13 10 23 30.3 50 - 59 6 11 17 22.4 ≥ 60 9 8 17 22.4 Total 38 38 76 100 X ± SD 47.24 ± 13.98 48.71 ± 12.99 47.97 ± 13.43 The mean age of the study group was 47.97 ± 13.43. The age ranged from 21 to 77. The group of 40 - 49 years old made up the highest proportion (30.3%). Patients older than 40 years old were predominant (75.1%). Male to female ratio was 1/1. There was no significant difference in mean age of male to female (p = 0.64). Journal of military pharmaco-medicine n o 1-2019 168 Nguyen Khac Kiem (2010) conducted a study on 71 patients showed that the age ranged from 15 to 75, and patients at the age of 30 - 50 accounted for the majority with 56.3% [1]. In a studying on 209 patients with thymoma, Huynh Quang Khanh reported that the mean age was 44.30 ± 15.15 years old, patients aged 31 - 60 were predominant, there was no difference between genders. Thus, most of studies revealed that thymoma occurred in adults. There was no sex predominant. Table 2: Tumor size. Size (cm) n % ≤ 5 60 78.9 5 - 10 14 18.4 > 10 2 2.7 Total 76 100 X ± SD 4.09 ± 2.27 Mean tumor size was 4.09 ± 2.27, ranged from 0.5 to 12 cm. According to Khanh's study, the mean tumor size was 8.17 ± 2.44 cm [2]. This difference comes from the different ways of choosing surgery methods. Our study involved both open and endoscopic thymectomy while Khanh’s study only involved open thymectomy. * Masaoka’s stage: + Noninvasive tumors (Masaoka I): 42 cases (55.3%) which was the most common. + Invasive tumors: 43 cases include: 25 cases (32.9%) with capsular invasion (Masaoka IIA), 6 cases (7.9%) extended into perithymic adipose tissue (Masaoka IIB) and 3 cases (3.9%) invaded to the lung parenchyma (Masaoka III) (the tumor invaded to the lung although the size was under 4 cm). This result was different from Huynh Quang Khanh’s, most cases (67.2%) had noninvasive tumors (stage I), 17.2% of cases had capsular invasion (stage II) and the percentage of tumors with perithymic tissue was 15.6% [2]. Table 3: Severity of clinical MG (Osserman's classification). Clinical features n % No MG 31 40.8 Class I 18 23.7 Class IIA 26 34.2 MG Class III 1 1.3 Total 76 100 45 cases (59.21%) had signs of MG. Class IIA was the most common (57.8%). Our result was higher than others’ finding. Pham Huu Lu’s research (2015) showed that MG was associated with 11.54% of patients with thymoma [3], this incidence was 36.5% in the Zhefeng Zhang's study (2016) [5]. Myasthenia gravis is the most common presentation among neuroimmune diseases associated with thymomas. The incidence of thymoma with MG ranges from 10 - 25%. The signs vary from time to time, there have been progressive and regressive periods alternatively. Signs of MG can manifest before or after thymectomy. Journal of military pharmaco-medicine n o 1-2019 169 The manifestation of MG is the presence of fatigable muscle weakness including ocular, facial, oropharyngeal or extremity muscle. The prostigmin test or the anti- acetylcholine receptor (AChR) antibody test can be used for diagnosing MG. Table 4: Pathological classification of thymomas. Type n % A 15 19.7 AB 18 23.8 B1 20 26.3 B2 20 26.3 B3 3 3.9 Total 76 100 Type B1 and B2 thymoma accounted for 26.3% separately and were the most common, type B3 (3.9%) was the least common. The incidence of type B3 thymoma was lower than Zhefeng Zhang’s results (18.4%) [5]. The other types were consistent with other researchers’ findings [10]. Table 5: Correlation between pathological types and MG. Clinical features Pathological type No MG MG Total % p A 6 9 15 19.7 AB 7 11 18 23.8 B1 8 12 20 26.3 B2 7 13 20 26.3 B3 3 0 3 3.9 0.519 Total 31 45 76 100 (χ² = 11.11, df = 12, p = 0.519) In some previous studies, there was the correlation between pathological types and MG, the incidence of MG was the highest in type B2. In our research, there was no statistically significant difference between pathological types and MG (p > 0.05). According to Zhefeng Zhang (2016), the incidences of correlation MG with types A, AB, B1, B2, B3 were 2.6%; 13.2%; 13.2%; 52.6% and 18.4%, respectively, type B2 thymoma was the most common (52.6%) [5]. Journal of military pharmaco-medicine n o 1-2019 170 Table 6: The expression of IHC markers in thymomas. Type A Type AB Type B1 Type B2 Type B3 Markers (+) (-) Σ (+) (-) Σ (+) (-) Σ (+) (-) Σ (+) (-) Σ CD3 7 1 8 16 1 17 18 0 18 15 2 17 2 0 2 CD20 0 7 7 2 12 14 10 7 17 3 14 17 1 0 1 CD45 2 2 4 8 0 8 7 0 7 6 0 6 1 0 1 CD117 2 4 6 0 1 1 0 4 4 1 4 5 AE1/AE3 14 1 15 17 0 17 14 3 17 19 0 19 3 0 3 EMA 2 3 5 5 3 8 1 3 4 1 4 5 2 0 2 CK19 3 1 4 1 1 2 7 0 7 Ki67 3 0 3 5 0 5 7 0 7 0 5 5 1 0 1 p53 3 4 7 1 0 1 1 1 2 1 3 4 0 0 0 - CD3 was positive in 100% of type B1 and B3 thymomas and most of types A, AB and B2 thymomas. - A small number of CD20-positive can be found in type AB and B2, CD20 was negative in type A. 58.8% of cases of type B1 thymoma reacted positively with CD20, which approved that type B1 thymoma tumor had the lymphocytic component which stained with CD20. - Most of cases showed positive staining for CD45 and CD3, this result demonstrated the lympho T - rich pattern in thymomas. - True to the epithelial origination, the neoplastic cells of thymomas were positive for CK AE1/AE3. This result was consistent with WHO 2015. - The positive expression of Ki67 in most of cases revealed the high proliferation activity of tumor cells, although some cases demonstrated weak positive results. - p53 revealed weak positive in 14 cases. - There have been difficulties in using IHC in thymomas because thymomas are neoplasms composed of many kinds of cells with varying numbers. Journal of military pharmaco-medicine n o 1-2019 171 Figure 1: Pathological types of thymomas: Type A (a); type B1 (b); type B2 (c) and type B3 (d). CONCLUSION - Generally, thymoma rarely exposes on children. Mean age 47.97 ± 13.43. There was no difference between genders. The tumor size was quite large, mean size 4.09 ± 2.27 cm. 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