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ObjectiveTo report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies.MethodsFrom January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients’ serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections.ResultsSerum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells.ConclusionsGFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.

Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG to explore their clinical presentations and determine whether the presence of autoimmune diseases affects the disease severity and treatment strategies for MG. We reviewed all the major immune-mediated coexisting autoimmune conditions associated with MG. PubMed, Embase and Web of Science were searched for relevant studies from their inception to January 2023. There is a higher frequency of concomitant autoimmune diseases in patients with MG than in the general population with a marked risk in women. Most autoimmune comorbidities are linked to AChR-MG; however, there are few reports of MuSK-MG. Thyroid disorders, systemic lupus erythematosus, and vitiligo are the most common system autoimmune diseases associated with MG. In addition, MG can coexist with neurological autoimmune diseases, such as neuromyelitis optica (NMO), inflammatory myopathy (IM), multiple sclerosis (MS), and autoimmune encephalitis (AE), with NMO being the most common. Autoimmune diseases appear to develop more often in early-onset MG (EOMG). MS coexists more commonly with EOMG, while IM coexists with LOMG. In addition, MG complicated by autoimmune diseases tends to have mild clinical manifestations, and the coexistence of autoimmune diseases does not influence the clinical course of MG. The clinical course of neurological autoimmune diseases is typically severe. Autoimmune diseases occur most often after MG or as a combined abnormality; therefore, timely thymectomy followed by immunotherapy could be effective. In addition, thymoma-associated AChR MG is associated with an increased risk of AE and IM, whereas NMO and MS are associated with thymic hyperplasia. The co-occurrence of MG and autoimmune diseases could be attributed to similar immunological mechanisms with different targets and common genetic factor predisposition. This review provides evidence of the association between MG and several comorbid autoimmune diseases.

Patients with synchronous tonsillar squamous cell carcinoma (SCC) and mediastinal thymoma are exceedingly rare. We present this case to highlight the diagnostic challenges and complex treatment decisions required when managing dual primary malignancies. A 63-year-old man presented with a 4-week history of throat discomfort. Initial examination revealed a right tonsillar mass, a mediastinal mass, and mild elevation of the left hemidiaphragm. A biopsy of the tonsil demonstrated p16-positive SCC, and a computed tomography (CT)-guided needle biopsy of the mediastinal mass revealed a thymoma, type AB. Following a multidisciplinary tumor board discussion, the patient underwent definitive external beam radiotherapy to the oropharynx [66 gray (Gy) in 33 fractions over 50 days] with concurrent high-dose cisplatin chemotherapy. Despite supportive measures, coronavirus disease (COVID-19) pneumonia occurred one-month post-radiotherapy, exacerbating his respiratory compromise. Six months later, he received a robotic-assisted thymectomy and lung wedge resection for the thymoma, during which the involved phrenic nerve was meticulously preserved. Histopathology confirmed malignant thymoma without metastasis. The patient recovered very well. However, recurrent COVID-19 infection and multifocal pneumonia two months post-surgery deteriorated his respiratory status, leading to home hospice care. To the best of our knowledge, this is the first documented case with synchronous tonsillar SCC and mediastinal thymoma. This case underscores the complexity of treating synchronous malignancies and illustrates how multidisciplinary collaboration is pivotal for optimal outcomes, particularly when managing evolving complications and balancing aggressive therapies against overall patient well-being.

Abstract Thymomas are benign thymic epithelial neoplasms, rarely found outside the anterior mediastinum. Although hyperthyroid states have been associated with thymic hyperplasia, only 3 thymoma cases have been previously reported in patients with Graves disease (GD), all within the anterior mediastinum. Here, we report a case of ectopic cervical thymoma in a 22-year-old female patient previously treated for GD. The patient underwent ultrasonography, computed tomography, inconclusive fine-needle aspiration, and ultimately gross dissection for diagnostic workup and definitive treatment of an anterior neck mass, producing a 2.5 × 2.3 × 1.5-cm entity consistent with Masaoka stage I and type B2 thymoma per World Health Organization classification. The patient underwent an uncomplicated subsequent clinical course, with no adjuvant radiotherapy administered. After conducting a systematic literature review, we conclude that of the 109 cases of ectopic cervical thymoma reported, this is the first to describe a case of ectopic cervical thymoma in a patient with a past medical history of GD. For GD patients in stable euthyroid remission with the persistent or recurrent presence of an anterior neck mass, the extrathyroidal origin of the mass should always be considered, including the exceptional presence of a cervical ectopic thymoma.

Background To identify the associations between thymic pathology and the prognosis of myasthenia gravis (MG) patients. Methods In this multicenter retrospective study, 1,254 myasthenia gravis (MG) patients who underwent thymectomy across four clinical centers were included. Participants were categorized by thymic pathology into thymomatous and non-thymomatous groups. Primary outcome was postoperative deterioration. Secondary outcomes comprised the proportion of patients achieving minimal manifestation status (MMS) within the first year after surgery and conversion from ocular MG (OMG) to generalized MG (GMG) within 2 years of symptom onset. Subgroup analyses assessed associations between world health organization (WHO) pathological type (both groups) or Masaoka stage (thymoma patients) and prognosis. Results Thymomas were associated with an increased risk of deterioration in both Cox regression (adjusted HR = 1.40 [1.18, 1.66], p  < 0.001) and logistic regression analyses (1-year deterioration: adjusted OR = 1.59 [1.15, 2.20], p  = 0.005; 3-year deterioration: adjusted OR = 1.40 [1.01, 1.94], p  = 0.047). Additionally, thymomas were linked to a higher conversion rate (adjusted OR = 2.37 [1.15, 4.86], p  = 0.019). However, thymoma showed no significant association with MMS (adjusted p  = 0.682). In the thymoma subgroup, neither pathological type nor Masaoka stage was significantly associated with deterioration (pathological type: 1-year p  = 0.069, 3-year p  = 0.220; Masaoka stage: 1-year p  = 0.944, 3-year p  = 0.909), first-year MMS attainment (pathological type: p  = 0.067; Masaoka stage: p  = 0.579), or conversion rate (pathological type: p  = 0.606; Masaoka stage: p  = 0.163). Similarly, in the nonthymomatous group, WHO pathological type was not significantly correlated with deterioration (1-year p  = 0.806, 3-year p  = 0.654), MMS achieved ( p  = 0.940), or conversion ( p  = 0.755). Conclusions This study demonstrated an association between thymoma and higher risks of clinical deterioration, which was independent of WHO pathological type or Masaoka stage.

Introduction Thymic epithelial tumors (TETs) are rare neoplasms often associated with immune-related disorders. Patients with Good’s syndrome (GS), an adult-acquired TET-related immunodeficiency, are at a high risk of mortality due to infectious diseases. This study aims to examine COVID-19 occurrence and severity in TET patients, with or without GS. Methods Clinical records of TET patients referred to the Regional Coordinating Center for Rare Tumors of Campania Region were retrospectively collected. During the observation period, elapsing from March 2020 to April 2023, the following data were collected: occurrence of SARS-CoV-2 infection; COVID-19 severity, according to the National Institute of Health (NIH) illness categories; COVID-19 treatment. COVID-19 occurrence and severity were assessed in the overall population and correlated with the presence of GS and/or other immune-related dysregulations. Results Overall, 47 TET patients were included in the study; 27 of these (57.4%) had GS. All participants had received a full cycle of mRNA vaccine for SARS-CoV2., Thirty-one patients (66.0%) experienced COVID-19, of whom 18 (58.0%) had previously received a diagnosis of GS. No significant association of GS and/or other immune-related dysregulations with SARS-CoV-2 infection occurrence was detected (Fisher’s exact test p  = 1 and p  = 0.3587, respectively). Among patients with GS, 8 (45.0%) reported a COVID-19 severity score of ≥ 3; whereas, only 1 of the 13 patients without GS (7.7%) had a severity score of ≥ 3. The correlation between presence of GS and COVID-19 severity (score 1 or 2 vs. ≥ 3) was statistically significant ( p  = 0.0448). No statistically significant association between COVID-19 severity and other immune-related syndromes were found ( p  = 1). Of note, all the hospitalized patients for NIH 4 and 5 COVID-19 had GS. Conclusions Our data suggest that TET patients, especially those with GS, require a careful multidisciplinary monitoring for SARS-CoV-2 infection, in order to establish tailored treatments and prophylactic protocols.

Myasthenia gravis (MG) is an immune-mediated disease frequently associated with thymic changes. Increased T helper 17 (Th17) cell activity and dysfunctional regulatory T (Treg) cells have been demonstrated in subgroups of MG. On the other hand, hypoxia-inducible factor 1 (HIF-1) has been shown to regulate the Th17/Treg balance by inducing Th17 differentiation while attenuating Treg development. To identify the underlying mechanisms of different thymic pathologies in MG development, we evaluated thymic samples from thymoma-associated myasthenia gravis (TAMG), MG with hyperplasia (TFH-MG) and thymoma without MG (TOMA) patients. Differential gene expression analysis revealed that TAMG and TFH-MG cells are associated with different functional pathways. A higher RORC/FOXP3 ratio provided evidence for Th17/Treg imbalance in TAMG potentially related to increased HIF1A . The hypoxic microenvironment in thymoma may be a driver of TAMG by increasing HIF1A . These findings may lead to new therapeutic approaches targeting HIF1A in the development of TAMG.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against “self”. In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients’ life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

Background and purpose Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma‐associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. Methods We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC‐positive and GC‐negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. Results Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC‐positive, whereas 175 were GC‐negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC‐positive group than in the GC‐negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358–105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029–0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742–67.000) were significantly associated with postthymectomy MG. Conclusions Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.