Long-term outcomes of robot-assisted radical thymectomy for large thymomas: A propensity matched analysis.

BACKGROUND: The aim of this study was to evaluate the long-term results of robot-assisted (RATS) thymectomy in the treatment of large thymomas, defined as larger than 5 cm. METHODS: We retrospectively reviewed 106 thymectomies from 2010 to 2020, creating two groups based on the surgical approach (open or RATS) and size. Kaplan-Meier and Cox-regression were used to estimate and identify risk factors of oncological outcomes. To perform a well-balanced analysis, a propensity score matched (PSM) analysis was conducted for large thymomas. RESULTS: From 2015, we performed 54 RATS thymectomies: 53.7% (n = 29) for small and 46.3% (n = 25) for large thymomas. Conversions were similar and all patients had a complete resection. The overall (82% vs. 92%, p = 0.57) and disease-free survival were comparable between RATS and open (92.5% vs. 93%, p = 0.67), outcomes confirmed after PSM for large thymomas. CONCLUSIONS: RATS thymectomy could be considered a valid option in selected patients with large thymomas.

Immunodeficiency and thymoma in Good syndrome: Two sides of the same coin.

Good Syndrome is a rare clinical entity first described as the conjunction of thymoma and hypogammaglobulinemia, and more recently depicted as a complex disease integrating a medical history of thymoma with humoral immunodeficiency (more accurately stated: hypogammaglobulinemia) with or without cellular immunodeficiency, recurrent infections, autoimmunity, paraneoplastic syndromes and diverse aberrations in the immunological profile. This condition has an ominous prognosis with a high mortality rate secondary to recalcitrant infectious diseases. Understanding the possible discordances in clinical presentation and the temporal relationship between manifestations and immunological alterations is key to prevent misdiagnosis and complications. To this end, here we provide two illustrative patients with Good Syndrome that share common clinical manifestations and yet show unique and opposed immunological profiles, thereby highlighting the pivotal interest of a comprehensive immunological profiling in these patients. We conducted a thorough review of existing literature on the elusive molecular mechanisms underlying the syndrome and provide a clinical assessment algorithm to facilitate the management of these challenging patients.

Thymoma-associated myasthenia gravis: Clinical features and predictive value of antiacetylcholine receptor antibodies in the risk of recurrence of thymoma.

BACKGROUND: Thymoma-associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR-Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR-Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses. METHODS: We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post-thymectomy status, oncological features and surgical approach. AChR-Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR-Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence. RESULTS: The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow-up time: 4.8 years). The AChR-Ab titers decreased after first thymectomy (P < 0.001); the decrease was more pronounced in female patients (P = 0.05), in patients diagnosed with MG at an older age (P = 0.003), and in those who had lower MG stage before surgery (P = 0.02) or higher Masaoka-Koga stage (P = 0.005). The risk of relapse was closely linked with the age of the patient, the Masaoka-Koga stage and the surgical approach. CONCLUSIONS: Presurgery levels of AChR-Ab or their change after surgery were not associated with thymoma recurrence. The reduction of AChR-Ab titers after thymectomy confirms an immunological role of thymoma in the pathogenesis of MG. KEY POINTS: Significant findings of the study: Young MG patients with an advanced Masaoka staging score of the primary tumor who underwent thymectomy with approaches different from sternotomy and VATS should be monitored for high risk of recurrence. WHAT THIS STUDY ADDS: No other study has ever investigated the changes in AChR-Ab titers before and after thymectomy in a large cohort of TAMG patients. The reduction of AChR-Ab titers after thymectomy suggests an immunological role of thymoma in the pathogenesis of MG.

Preferentially expressed antigen in melanoma as a novel diagnostic marker differentiating thymic squamous cell carcinoma from thymoma.

Thymic squamous cell carcinoma (TSQCC), accounting for 70-80% of thymic carcinoma cases, is distinct from thymoma. However, differential diagnosis for type B3 thymoma is sometimes challenging, even with established markers for TSQCC, including KIT and CD5, which are expressed in ~ 80% of TSQCCs and ~ 3% of thymomas. Novel TSQCC-specific markers would facilitate precise diagnosis and optimal treatment. Herein, we found that preferentially expressed antigen in melanoma (PRAME) may be a novel TSQCC-specific diagnostic marker. We comprehensively profiled 770 immune-related mRNAs in 10 patients with TSQCC and two healthy controls, showing that PRAME and KIT were significantly upregulated in TSQCC (adjusted p values = 0.045 and 0.0011, respectively). We then examined PRAME expression in 17 TSQCCs and 116 thymomas via immunohistochemistry. All 17 (100%) TSQCCs displayed diffuse and strong PRAME expression, whereas eight of 116 (6.8%) thymomas displayed focal and weak expression (p < 0.0001). KIT and CD5 were positive in 17 (100%) and 16 (94.1%) TSQCCs, respectively, whereas one (0.9%) type B3 thymoma showed double positivity for KIT and CD5. The KIT-/CD5-positive type B3 thymoma was negative for PRAME. Thus, combinatorial evaluation of PRAME with KIT and CD5 may facilitate a more precise diagnosis of TSQCC.

Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.

BACKGROUND: Thymic epithelial tumors are PD-L1-expressing tumors of thymic epithelial origin characterized by varying degrees of lymphocytic infiltration and a predisposition towards development of paraneoplastic autoimmunity. PD-1-targeting antibodies have been evaluated, largely in patients with thymic carcinoma. We sought to evaluate the efficacy and safety of the anti-PD-L1 antibody, avelumab (MSB0010718C), in patients with relapsed, advanced thymic epithelial tumors and conduct correlative immunological studies. METHODS: Seven patients with thymoma and one patient with thymic carcinoma were enrolled in a phase I, dose-escalation trial of avelumab (MSB0010718C), and treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Tissue and blood immunological analyses were conducted. RESULTS: Two of seven (29%) patients with thymoma had a confirmed Response Evaluation Criteria in Solid Tumors-defined partial response, two (29%) had an unconfirmed partial response and three patients (two thymoma; one thymic carcinoma) had stable disease (43%). Three of four responses were observed after a single dose of avelumab. All responders developed immune-related adverse events that resolved with immunosuppressive therapy. Only one of four patients without a clinical response developed immune-related adverse events. Responders had a higher absolute lymphocyte count, lower frequencies of B cells, regulatory T cells, conventional dendritic cells, and natural killer cells prior to therapy. CONCLUSION: These results demonstrate anti-tumor activity of PD-L1 inhibition in patients with relapsed thymoma accompanied by a high frequency of immune-related adverse events. Pre-treatment immune cell subset populations differ between responders and non-responders. TRIAL REGISTRATION: ClinicalTrials.gov - NCT01772004 . Date of registration - January 21, 2013.

Tobacco smoking and alcohol consumption as risk factors for thymoma - A European case-control study.

PURPOSE: Hardly anything is known about the aetiology of thymoma. This paper presents data regarding tobacco smoking and alcohol consumption in relation to thymoma from the first case-control study performed on this rare tumour. METHODS: A European multi-centre case-control study including incident cases aged 35-69 years with thymoma between 1995 and 1997, was conducted in seven countries. A set of controls, used in seven parallel case-control studies by the same research group was used, including population-based controls from five countries and hospital controls with colon cancer from two countries. Altogether 103 cases, accepted by a reference pathologist, 712 colon cancer controls, and 2071 population controls were interviewed. RESULTS: Tobacco smoking was moderately related with thymoma (OR 1.4, 95% CI 0.9-2.2), and a tendency to dose-response was shown (p = 0.04), with an increased risk for heavy smokers defined as ≥41 pack-years (OR 2.1, 95% CI 1.1-3.9). A high consumption of spirits defined as ≥25 g of alcohol per day was associated with an increased risk of thymoma (OR 2.4, 95% CI 1.1-5.4), whereas no association was found with beer or wine. CONCLUSIONS: Tobacco smoking and a high intake of spirits were indicated as risk factors for thymoma.

Thymoma associated myasthenia gravis with atypical presentation of lipomatous tongue atrophy: a case report.

A 28-year-old female patient came to the outpatient dental clinic for multiple teeth extractions and full mouth rehabilitation suffer from myasthenia gravis (MG) primary presentation as tongue atrophy and facial muscles weakness and the symptoms became worries, the patient unable to speak as well and change her voice and complaining of dysphagia and dysarthria. Oral symptoms, treatment schedule and protocol, the selection, prescription and impacts of medications, and prevention of myasthenic crisis are all important; aspects should be considered by dentists and oral health care providers. Weakness of facial and oropharyngeal muscle is considered very popular at disease onset and therefore oral health providers are often the first medical professionals to observe these patients. Myasthenic patients seek particular approach and consultation in order to ensure ideal and proper dental management.

Clinical analysis of Chinese anti-low-density-lipoprotein-receptor-associated protein 4 antibodies in patients with myasthenia gravis.

BACKGROUND AND PURPOSE: Low-density-lipoprotein-receptor-associated protein 4 (LRP4) autoantibodies have recently been detected in myasthenia gravis (MG), but little is known about the clinical characteristics associated with this serological type. In this study, the clinical features of Chinese patients with anti-LRP4 antibody-positive MG were characterized. METHODS: A total of 2172 MG serum samples were collected from patients in various parts of China. An enzyme-linked immunosorbent assay was used to detect acetylcholine receptor (AChR) antibody and titin antibody, and cell-based assays were used to detect muscle-specific kinase antibody and LRP4 antibody. Clinical data for patients with MG were collected from different provinces in China. RESULTS: In total, 16 (0.8%) patients with LRP4-MG were found amongst 2172 total patients, including three patients with AChR/LRP4-MG. Additionally, 13 (2.9%) patients with LRP4-MG were found amongst 455 patients with double seronegative MG. The ratio of males to females for these 13 patients was 1:1.6, and 53.8% patients were children. A total of 91.7% of cases exhibited initial ocular involvement, and 58.3% of cases exhibited simple eye muscle involvement. Responses to acetylcholinesterase inhibitors and prednisone were observed. CONCLUSION: The expanded sample confirmed that the positive rate of LRP4 antibodies in China is lower than that in western countries. Our results highlighted the differences between LRP4-MG and other antibody groups. Children and female patients with LRP4-MG have a higher prevalence, often involving the ocular muscles and limb muscles. The clinical symptoms are mild, and satisfactory responses to treatment are often achieved.

El timoma, ¿es una enfermedad sistémica? / Thymoma. A Systemic Disease?

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Immunodeficiency associated with tumour pathology: Good's syndrome.

The Good's syndrome (GS) is a low prevalence entity where thymoma often is associated with immunodeficiency. Patients may start presenting recurrent rhinosinusal infections, bronchopulmonary infections, haematological alterations and diarrhoea, secondary to immunodeficiency. They can also present respiratory symptoms and parathymic syndromes derived from the existence of thymoma, a slow-growing neoplasm located in the anterior mediastinum. We present the case of a 76-year-old man diagnosed with thymoma by image analysis, which had presented multiple episodes of pneumonia and two admissions to the hospital for diarrhoea of weeks of evolution. After finishing the study, the patient is diagnosed of GS. In this case, thymectomy prevented the appearance of parathymic syndrome, but without any effect on immunodeficiency symptoms. To decrease repeat infections, substitution therapy with immunoglobulins was started. The prognosis will depend mainly on the recurrent infectious and to a lesser extent on the thymic neoplasm.

Seronegative Paraneoplastic Limbic Encephalitis Associated with Thymoma.

Paraneoplastic limbic encephalitis is an autoimmune syndrome characterized by the acute or subacute onset of encephalopathy, memory loss, confusion, temporal lobe seizures, and behavioral and mood changes. Although most patients with paraneoplastic limbic encephalitis have antineuronal antibodies, advances in the field now permit the diagnosis without autoantibody test results. In this case illustrating the new diagnostic criteria, we report a 70-year-old woman who was brought to the emergency room after the acute onset of cognitive impairment, altered mental status, and choreoathetoid movements. Brain magnetic resonance imaging showed hyperintense signals in both temporal lobes, and a chest computed tomogram revealed a thymoma. Because the patient met current diagnostic criteria for autoimmune limbic encephalitis, we were able to start treatment before her antibody tests were processed. The patient received immunotherapy and her tumor was resected. Her choreoathetoid movements disappeared and her other neurologic symptoms improved. Her cerebrospinal fluid proved to be negative for paraneoplastic limbic encephalitis antibodies. Most but not all patients with paraneoplastic limbic encephalitis associated with thymoma have evidence of paraneoplastic antibodies. Prompt management of the underlying malignancy determines whether patients survive and may minimize future cognitive and functional impairment. Practicing neurologists and psychiatrists should be aware of this diagnosis.

CXCR4 overexpression correlates with poor prognosis in myasthenia gravis-associated thymoma.

Thymoma is 1 rare type of tumor developed on the thymic epithelium; patients with thymoma also might have myasthenia gravis (MG). Because of the scarcity and complexity of MG-associated thymoma, its pathogenesis and etiology still remain unclear nowadays. The expression of C-X-C chemokine receptor type 4 (CXCR4) is absent or low in most healthy tissues but highly expressed in various types of tumors. Here, to determine the prognostic significance of CXCR4 in MG-associated thymoma, a total of 84 tissue samples were retrospectively examined. Our data demonstrated that CXCR4 was strongly associated with worse overall survival (hazard ratio, 2.11; 95% confidence interval, 1.08-4.11) and disease-free survival (hazard ratio, 1.84; 95% confidence interval, 1.03-3.29). Furthermore, both univariate and multivariate analyses confirmed that CXCR4 was an independent factor in predicting unfavorable overall survival. In conclusion, our findings suggest that CXCR4 might contribute to the clinical cancer progression, and CXCR4 could be a valuable prognostic biomarker in the therapy of MG-associated thymoma.

Acquired T-Cell Immunodeficiency in Thymoma Patients.

Acquired T-cell immunodeficiency can occur in thymoma patients with or without hypogammaglobulinemia (Good's syndrome), but it has received little attention to date. It appears predominantly associated with lymphocyte-rich (i.e., cortical or mixed) thymomas and frequently coexists with autoimmune manifestations. The main abnormalities are an increase in circulating naive T cells, cutaneous T-cell anergy, TCR hyporesponsiveness in vitro as well as a numerical and functional impairment of regulatory T cells. All of these probably result from an abnormal T-cell maturation in the neoplastic thymic microenvironment. A better understanding of thymoma-related acquired T-cell immunodeficiency will be important for immunotherapy of this orphan disease as well as for the prevention and treatment of opportunistic infections, autoimmune complications and secondary malignancies that contribute to the morbidity and mortality of thymoma patients.

Thymoma associated with autoimmune diseases: 85 cases and literature review.

OBJECTIVES: To describe the clinical features, treatment, and outcome of autoimmune diseases (AD) in a cohort of patients with thymoma. DESIGN: Pathological records from three university hospitals, between 2005 and 2011, were reviewed to identify patients with thymoma. Patients with thymoma and AD were compared with patients with thymoma without AD. RESULTS: 47/85 (55%) cases of thymoma had AD, including myasthenia gravis (MG) (n=33), Hashimoto's thyroiditis (n=4), Isaac's syndrome (n=3), Morvan syndrome (n=2), pure red cell aplasia (n=2), systemic lupus (n=2), lichen planus (n=2), and one case of each following conditions: aplastic anemia, autoimmune hemolytic anemia, Good's syndrome, pemphigus, autoimmune hepatitis, Graves' disease, limbic encephalitis, and inflammatory myopathy. Six patients (7%) presented at least 2 ADs. The median duration of follow-up after surgery was 60 months (40-78 months). In 32 patients, the diagnosis of AD preceded the diagnosis of thymoma, in 9 patients, thymoma was diagnosed at the same time as the AD and 7 patients had been operated on when they developed an AD. We found a significative difference on the Masaoka stage between the MG patients and the patients who present another AD (p=0.028). No risk factor for developing an AD after thymectomy was identified. CONCLUSIONS: We describe here the long-term follow-up of a large series of AD related to thymoma. Our results confirm previous data concerning AD occurrence in patients with thymoma and suggest that preexisting autoimmunity is not a risk factor for developing autoimmune manifestations after thymectomy.

Inferior oblique muscle paresis as a sign of myasthenia gravis.

Myasthenia gravis may affect any of the six extra-ocular muscles, masquerading as any type of ocular motor pathology. The frequency of involvement of each muscle is not well established in the medical literature. This study was designed to determine whether a specific muscle or combination of muscles tends to be predominantly affected. This retrospective review included 30 patients with a clinical diagnosis of myasthenia gravis who had extra-ocular muscle involvement with diplopia at presentation. The diagnosis was confirmed by at least one of the following tests: Tensilon test, acetylcholine receptor antibodies, thymoma on chest CT scan, or suggestive electromyography. Frequency of involvement of each muscle in this cohort was inferior oblique 19 (63.3%), lateral rectus nine (30%), superior rectus four (13.3%), inferior rectus six (20%), medial rectus four (13.3%), and superior oblique three (10%). The inferior oblique was involved more often than any other muscle (p<0.01). Eighteen (60%) patients had ptosis, six (20%) of whom had bilateral ptosis. Diagnosing myasthenia gravis can be difficult, because the disease may mimic every pupil-sparing pattern of ocular misalignment. In addition diplopia caused by paresis of the inferior oblique muscle is rarely encountered (other than as a part of oculomotor nerve palsy). Hence, when a patient presents with vertical diplopia resulting from an isolated inferior oblique palsy, myasthenic etiology should be highly suspected.

Thymoma complicated by acquired amegakaryocytic thrombocytopenia and pure red cell aplasia.

Although the association of pure red cell aplasia (PRCA) and aplastic anemia with thymoma is well-known, acquired amegakaryocytic thrombocytopenia (AAMT) is not a recognized paraneoplastic manifestation of thymoma. This report discusses a patient with recurrent thymoma complicated by myasthenia gravis, PRCA, and AAMT. Both PRCA and AAMT are diagnosed after a thymoma recurrence, 11 years after complete resection of the initial tumor and 9 months after chemotherapy for the relapsed disease. Both PRCA and AAMT responded to immunosuppression with cyclosporine, corticosteroid, and an abbreviated course of antithymocyte globulin, achieving a very good erythroid response and a complete remission for AAMT, suggesting that AAMT, although extremely rare, can be an immune-mediated paraneoplastic manifestation of thymoma.

Successful salvage chemotherapy with amrubicin for invasive thymoma associated with myasthenia gravis.

Anthracycline-based regimens with cisplatin have been commonly used for inoperable and relapsed thymoma. However, little information is available regarding the usefulness of salvage chemotherapy. Here, we describe a case of invasive thymoma associated with myasthenia gravis that showed a marked response to third-line chemotherapy, with single-agent amrubicin, a synthetic anthracycline analog and potent deoxyribonucleic acid topoisomerase II inhibitor. Amrubicin appears to have significant activity against invasive thymoma.