Thymoma; clinical presentations, pathology, and prognostic factors – a surgery point of view

Thymomas are rare tumors that can present with a wide range of clinical characteristics. The presence of symptoms and paraneoplastic syndromes, such as myasthenia gravis, along with the histological subtype and stage of the tumor, are important factors that guide the treatment approach and prognosis for patients with thymomas. The prognosis for thymoma varies depending on several factors, including the stage and type of the tumor, as well as the presence of associated autoimmune diseases. Generally, early-stage thymomas have a better prognosis compared to advanced-stage tumors. Regular follow-up with a multidisciplinary team, including oncologists and thoracic surgeons, is essential for long-term management and surveillance of patients.


Introduction
Thymoma is a type of tumor arising from the thymus's epithelial cells. The thymus is responsible for the development and maturation of T-cells, a type of white blood cell involved in immune response (1). Pathologically, thymomas are characterized by the presence of abnormal epithelial cells within the thymus. These cells form various patterns, including spindle cells, round cells, or a mixture of both. The tumor can also contain lymphocytes, which are immune cells (2). Thymomas are classified into different subtypes based on their histological appearance. The World Health Organization (WHO) classification system categorizes thymomas into five types: A, AB, B1, B2, and B3. These subtypes are based on the proportion of lymphocytes and epithelial cells present in the tumor (3). Type A thymomas have a predominantly lymphocytic composition, with few or no epithelial cells. Type AB thymomas have a mixture of lymphocytes and epithelial cells, with a predominance of lymphocytes (4). Type B1 thymoma has a variety of lymphocytes and epithelial cells, with a predominance of epithelial cells. Type B2 thymomas have a higher proportion of epithelial cells compared to lymphocytes. Type B3 thymomas have a predominantly epithelial composition, with few or no lymphocytes (2,5).
The exact molecular mechanisms underlying the development of thymoma have yet to be fully understood. However, genetic mutations are believed to play a role in the initiation and progression of thymomas. Mutations in genes such as TP53, CDKN2A, and KIT have been identified in some cases of thymoma. These mutations can disrupt normal cellular processes, leading to uncontrolled growth and division of cells (6,7). Thymomas are often associated with autoimmune diseases, such as myasthenia gravis. In these cases, it is thought that the abnormal epithelial cells in the thymoma trigger an immune response, leading to the production of autoantibodies that attack muscle cells or other tissues (8,9). Autoimmune diseases can influence thymoma's clinical presentation and prognosis (1). Diagnosis of thymoma involves a combination of imaging studies, such as chest X-rays or computerized tomography, and tissue biopsy. A biopsy is necessary to confirm the presence of abnormal cells and determine the type and stage of the tumor (10). This review study aims to provide a comprehensive understanding of the histopathological DOI: 10.34172/ipp.2023.40581 with thymoma and myasthenia gravis, as it can improve symptoms and disease control. Since thymomas located in the anterior mediastinum can cause symptoms related to compression or invasion of nearby structures. These symptoms may include chest pain, cough, shortness of breath and difficulty breathing, or a feeling of fullness in the chest (16,17). In addition, thymomas located in the superior mediastinum can compress the superior vena cava, a large vein that carries blood from the head, neck, and upper body to the heart. This compression can lead to a condition known as superior vena cava syndrome, which is characterized by swelling of the face, neck, and upper body, dilated veins in the chest or neck, difficulty breathing, and cough (18).
Furthermore, thymomas can produce certain substances that cause paraneoplastic syndromes, a group of symptoms that occur due to the tumor's effect on distant organs or tissues. These syndromes can include endocrine abnormalities (such as Cushing's syndrome or hypoglycemia), hematological abnormalities (such as pure red cell aplasia), or other systemic symptoms. However, the clinical presentation of thymoma can vary significantly from person to person, and some individuals may only experience symptoms once the tumor has reached an advanced stage (19). Therefore, individuals must undergo regular medical check-ups and screenings to detect thymoma at an early stage when treatment outcomes are generally more favorable.

Paraneoplastic syndromes associated with thymoma
Thymoma is a rare type of tumor arising from the thymus gland, located in the chest behind the breastbone (sternum). While thymomas are typically slow-growing and often benign, they can be associated with various paraneoplastic syndromes. Paraneoplastic syndromes are a group of disorders that occur due to substances produced by the tumor affecting distant organs or tissues (20).
One of the most common paraneoplastic syndromes associated with thymoma is myasthenia gravis. Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigue. It occurs when antibodies the immune system produces mistakenly attack proteins involved in nerve-muscle communication.
In thymoma-associated myasthenia gravis, the tumor produces proteins that resemble those involved in nervemuscle communication, producing autoantibodies and subsequent muscle weakness.
Another paraneoplastic syndrome seen in patients with thymoma is pure red cell aplasia. This condition is a condition characterized by a decrease in red blood cell production, leading to severe anemia. In thymomaassociated pure red cell aplasia, it is believed that the tumor produces factors that suppress red blood cell production in the bone marrow (21,22).
Other paraneoplastic syndromes associated with

Key point
Thymoma can be associated with paraneoplastic syndromes, including myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, dermatomyositis, and systemic lupus erythematosus. These syndromes can provide important clues for diagnosing and managing patients with thymoma. The treatment of thymoma involves a combination of surgery, radiation therapy, chemotherapy, and emerging targeted or immunotherapies. The optimal treatment approach depends on various factors and should be tailored to each patient. Ongoing research and clinical trials continue to explore new treatment strategies and improve outcomes for individuals with thymoma.
thymoma included hypogammaglobulinemia, which is characterized by low levels of immunoglobulins (antibodies) in the blood, and dermatomyositis, an inflammatory muscle disease and also systemic lupus erythematosus, an autoimmune disorder affecting multiple organs (9,23). The presence of these paraneoplastic syndromes can often aid in the diagnosis of thymoma. However, all patients with thymoma will develop these syndromes, and their presence does not necessarily indicate malignancy. Additionally, treating these syndromes often involves addressing the underlying tumor, such as surgical removal of the thymoma or chemotherapy (9,24).

Outcomes of thymoma-associated myasthenia gravis
Thymoma-associated myasthenia gravis (MG) is a rare autoimmune disorder that affects the neuromuscular junction and is associated with the presence of a thymoma. The clinical course and outcomes of thymoma-associated MG can be variable, with some patients experiencing remission and others experiencing chronic disease with significant morbidity (25,26).
Diagnosing thymoma-associated MG requires a high index of suspicion, as symptoms may initially be attributed to other causes. Diagnostic testing typically includes serologic testing for acetylcholine receptor antibodies and imaging studies to evaluate for the presence of a thymoma. Management of thymoma-associated MG involves a combination of immunosuppressive therapy and surgical resection of the thymoma. These interventions' optimal timing and sequence are still a matter of debate, and individualized treatment plans are often necessary (25,27).
Long-term outcomes of thymoma-associated MG are variable, with some patients experiencing complete remission and others experiencing chronic disease with significant morbidity. Recurrence rates after thymectomy vary depending on the stage and histologic subtype of the thymoma, with higher rates observed in patients with more advanced disease (28,29).

Classification and staging of thymoma
Thymoma is a rare type of tumor that occurs in the thymus gland, located in the chest behind the breastbone (sternum). It can be classified and staged based on various factors, including the tumor cells' appearance, the tumor's invasiveness, and the cancer's spread (5). The classification and staging systems that are commonly utilized for thymoma encompass the following:

World Health Organization (WHO) classification
The WHO classification system classifies thymomas based on the appearance and behavior of the tumor cells. It includes the following subtypes; type A, type AB, type B1, type B2, type B3, and type C. Previous studies showed type A thymomas are the least aggressive, while type C thymomas are the most aggressive form (3,30,31).
• Stage I: The tumor is limited to the thymus and has not spread to surrounding structures • Stage II: The tumor has invaded nearby tissues or organs, but it can still be completely removed surgically • Stage III: The tumor has spread to nearby structures, such as the lungs, heart, or large blood vessels • Stage IVA: The tumor has spread to lymph nodes in the chest • Stage IVB: The tumor has spread to distant organs, such as the liver or bones.

TNM staging system
The TNM (tumor, node, and metastasis) system is a general staging system conducted for various types of cancer, including thymoma. It takes into account the size of the primary tumor (T), the presence or absence of regional lymph node involvement (N), and the presence or absence of distant metastasis (M). The TNM categories are further used to assign a stage to the thymoma (3,35,36).

Malignant thymoma
Malignant thymoma is a rare type of cancer that arises from the thymus gland. Treatment options include surgery, radiation therapy, chemotherapy, and targeted therapy. The prognosis for malignant thymoma varies depending on several factors, including the cancer stage, the type of tumor, and the patient's overall health (37,38). Surgery is the primary treatment for malignant thymoma; complete tumor resection is associated with better outcomes. Radiation therapy may be used in combination with surgery, as a stand-alone treatment for unresectable tumors, or as adjuvant therapy to reduce the risk of recurrence. Chemotherapy may also be used in advanced cases or as neoadjuvant therapy to shrink the tumor before surgery (19,39).
Several prognostic factors have been identified that can help predict the outcome of malignant thymoma. These include the cancer stage, the tumor's histological subtype, the presence of certain genetic mutations, and the patient's age and overall health (38,40).
Patients with early-stage tumors (stage I or II) and favorable histological subtypes (such as type AB or B1) have a better prognosis than those with more advanced disease or unfavorable subtypes (such as type B3 or C). The presence of certain genetic mutations, such as mutations in the TP53 gene, may also be associated with a poorer prognosis (41,42).
Age and overall health are also important prognostic Immunopathologia Persa Volume x, Issue x, 2023 4 factors. Younger patients and those with good performance status (a measure of general health and ability to carry out daily activities) tend to have better outcomes (43).

Molecular characteristics of thymomas
Molecular characterization of thymomas has provided valuable insights into the pathogenesis, classification, and potential therapeutic targets for this rare tumor.

TP53 mutations
Thymomas frequently harbor TP53 mutations associated with a more aggressive phenotype and poorer prognosis. TP53 mutations can be detected using molecular techniques such as sequencing or immunohistochemistry (46,47).

Genes associated with T-cell development
Thymomas arise from the thymic epithelial cells involved in T-cell development. Several genes involved in T-cell development have been found to be dysregulated in thymomas. For example, abnormalities in the WNT signaling pathway, including mutations in the CTNNB1 gene (encoding β-catenin), have been reported in a subset of thymomas (48,49).

Genes associated with immune regulation
Thymomas often exhibit dysregulated immune regulation, and several genes involved in immune response pathways have been implicated in thymoma development. For instance, alterations in the expression of genes involved in antigen processing and presentation, such as HLA class I and II molecules, have been reported (7,50).

Epigenetic alterations
Epigenetic modifications, including DNA methylation and histone modifications, play a crucial role in gene regulation. Thymomas have been shown to have distinct DNA methylation patterns compared to normal thymus. These epigenetic alterations can influence gene expression and contribute to the development of thymomas (51,52).

Potential therapeutic targets
The identification of molecular alterations in thymomas has led to the exploration of targeted therapies. For example, thymomas with mutations in the KIT gene may benefit from targeted therapy with tyrosine kinase inhibitors (such as imatinib). Additionally, inhibitors of the mTOR pathway (such as everolimus) have shown promise in thymomas with mTOR pathway dysregulation (7,55).

Treatment of thymoma
The primary treatment for thymoma is surgical resection, which aims to achieve complete tumor removal whenever possible. Thymectomy is also performed in patients with myasthenia gravis to alleviate symptoms. However, the treatment of thymoma depends on several factors, including the stage of the disease, the histological subtype of the tumor, and the overall health of the patient. Other main treatment modalities for thymoma include radiation therapy and chemotherapy. A combination of these treatments may sometimes be conducted (56,57).
Surgery is the primary treatment for thymoma and involves the complete removal of the tumor and surrounding tissue. The extent of surgery depends on the stage and location of the tumor. In early-stage thymoma, a complete and any involved surrounding structures are performed. This can be conducted through various surgical approaches, including open surgery or minimally invasive techniques such as video-assisted thoracoscopic or robotic-assisted surgery. In advanced cases, more extensive surgery may be required when the tumor has invaded nearby structures or metastasizes to distant sites (56,58).
Radiation therapy may be used as an adjuvant treatment following surgery or as a primary treatment for inoperable or recurrent thymoma. It involves the use of high-energy X-rays or other forms of radiation to kill cancer cells or inhibit their growth. Radiation therapy can be delivered externally (external beam radiation therapy) or internally (brachytherapy), depending on the specific situation and treatment goals (39,59).
Since chemotherapy is typically reserved for advanced or metastatic thymoma, as well as for unresectable tumors, the most commonly used chemotherapy regimens for thymoma include cisplatin-based combinations, such as cisplatin plus etoposide or cisplatin plus doxorubicin, chemotherapy can be administered before surgery (neoadjuvant chemotherapy) to shrink the tumor and improve resectability, after surgery (adjuvant chemotherapy) to reduce the risk of recurrence, or as palliative treatment to control symptoms and prolong survival (37,60).
In recent years, targeted therapies and immunotherapies have shown promise in treating advanced thymoma. Targeted therapies, such as tyrosine kinase inhibitors (e.g., sunitinib) or mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus), can inhibit specific molecular pathways involved in tumor growth and progression. Immunotherapies, such as immune checkpoint inhibitors (e.g., pembrolizumab or nivolumab), can enhance the immune system's ability to recognize and attack cancer cells. These therapies are still being investigated in clinical trials and may be combined with standard treatments (61,62).
The treatment choice for thymoma should be individualized based on the specific characteristics of the tumor and the patient's overall health. To develop a comprehensive treatment plan, multidisciplinary collaboration among surgeons, radiation oncologists, and medical oncologists is essential. Regular follow-up and surveillance are also important to monitor for disease recurrence or progression and to manage any long-term treatment-related complications (56,63).

Focus on the surgery for the thymoma: indications and results
As mentioned above, surgery is the primary treatment for thymoma and is indicated in most cases. The specific indications for surgery depend on the disease stage and the patient's overall health. In early-stage thymoma, surgery aims to remove the tumor completely and may involve a complete thymectomy along with any involved surrounding structures. This can be achieved through various surgical approaches, including open surgery or minimally invasive techniques such as video-assisted thoracoscopic or robotic surgery (19,56).
The surgery results for thymoma are generally favorable, with high rates of complete tumor resection and long-term survival. However, the prognosis can vary depending on factors such as the stage and histological subtype of the tumor, as well as the presence of any metastasis. Earlystage thymomas generally have a better prognosis than advanced-stage tumors (56,64).
Several studies have reported high rates of complete resection (R0 resection; surgical margin is microscopically negative for residual malignancy) with surgery alone, ranging from 80% to 100%. The 5-year survival rates for completely resected thymomas range from 70% to 90%, depending on the stage and histological subtype. However, even in cases where complete resection is impossible, surgery can still provide palliative benefits and improve quality of life (30,65).
In some cases, adjuvant therapies such as radiation therapy or chemotherapy may be used after surgery to reduce the recurrence risk or treat residual disease. The decision to use adjuvant therapies is based on factors such as the stage of the disease, the presence of certain high-risk features (e.g., invasion of surrounding structures), and the patient's overall health (63,66).

Conclusion
Surgery is the mainstay of treatment for thymoma and aims to achieve complete tumor resection. The surgery results for thymoma are generally favorable, with high rates of complete resection and long-term survival. Adjuvant therapies may be conducted in certain cases to reduce the recurrence risk or treat residual disease. However, the optimal treatment approach should be individualized based on the specific characteristics of the tumor and the patient's overall health.

Conflicts of interest
The authors declare that they have no competing interests.

Ethical issues
Ethical issues (including plagiarism, data fabrication, and double publication) have been completely observed by the authors.

Funding/support
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