Thymoma in Myasthenia Gravis for Ophthalmologists

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Myasthenia gravis (MG) may present to ophthalmologists and may be strictly ocular (OMG) at presentation. Up to 10-20% of patients with MG (generalized (GMG) or OMG) have an anterior mediastinal tumor, thymoma[1]. Thus, every patient with MG should undergo a computed tomography (CT) scan of the chest to rule out a thymoma. There is a risk of morbidity and mortality if thymoma progresses to a worse stage of the disease and a delayed diagnosis of thymoma can significantly increase mortality risk. Progressive local invasion of surrounding structures in the mediastinum can also lead to a 50% rate of recurrence if the surrounding great vessels are involved[2].

Staging

The most accepted staging system is the Masaoka-Koga staging of thymic tumors based on the level of invasion through the capsule, surrounding mediastinal fat and structures, and presence of metastasis primarily to the pericardium, pleura, and lungs[3][4]. A TNM classification system and several other were also developed; however, they are not widely accepted[5].

Masaoka-Koga Staging of Thymic Tumors
Stage Criteria
I Macroscopically and microscopically completely capsulated
II A Microscopic transcapsular invasion
II B Macroscopic invasion into the surrounding mediastinal fat tissue or grossly adherent to but not through the mediastinal pleura
III Invasion into neighboring organs
IV A Pleural or pericardial dissemination
IV B Lymphogenous or hematogenous metastases

Histology

The first histological staging system by Marino and Muller-Hermelink established six subtypes including medullary, mixed, predominantly cortical, cortical, well-differentiated thymic carcinoma (WDTC), and thymic carcinoma[6]. Later, the World Health Organization established a classification system based on the epithelial cell morphology and ratio of lymphocytes to epithelial cells. This system is widely validated and serves as an independent prognostic factor[7].

World Health Organization Histological Classification of Thymic Tumors
WHO Type Synonyms
A Spindle cell thymoma, medullary thymoma
AB Mixed thymoma
B1 Lymphocyte-rich thymoma, lymphocytic thymoma, predominantly cortical thymoma
B2 Cortical thymoma
B3 Well-differentiated thymic carcinoma, epithelial thymoma, squamoid thymoma
C Thymic carcinoma (heterogeneous)

Diagnostic Imaging

The evaluation of MG includes a CT scan of the chest with contrast to exclude thymic lesions including thymoma. CT is useful for differentiating thymoma and thymic hyperplasia through distinctive findings such as calcifications and signs of necrosis. This modality is also helpful for assessing invasion through the capsule and/or surrounding structures[8]. Histopathologic examination however may be necessary to definitively differentiate thymic hyperplasia from thymoma.

General treatment

The treatment of thymoma starts with surgical resection and depending on stage and grade of tumor may require chemotherapy or adjuvant therapy, or radiotherapy.

Surgical

Complete surgical resection, regardless of the stage, is the initial goal. However, if structural invasion hinders a complete resection, a partial resection is still recommended. The 10 and 5-year survival rates decrease, and 5-year recurrence rates increase as the tumor stage progresses.

Chemotherapy

Several studies have demonstrated a very high response rate to thymoma chemotherapy, and its addition to the treatment regimen is mostly dependent on the stage of the tumor. An unresectable tumor or recurrent tumor may benefit greatly from chemotherapy to decrease tumor size prior to surgery. It may also be used as a palliative measure to decrease a tumor’s progression. The regimen typically involves a platinum compound along with classic agents such as cyclophosphamide, doxorubicin, vincristine, and others.

Targeted therapies

Several studies have shown responses to targeted therapies including EGFR, VEGF, KIT and insulin-like growth factor 1R (IGF-1R) inhibitors.

Radiotherapy

Thymic tumors are typically responsive to radiotherapy. Stage II and more invasive tumors highly benefit where recurrence rates can decrease from 29-36% by adding radiotherapy to the treatment regimen[2].

Recurrence

Depending on the stage and histology of the tumor, recurrence rate can range from 5-50%. Recurrences are primarily pleural and usually multiple, so the use of minimally invasive procedures may decrease the recurrence rate by lowering the risk of pleural seeding. Once a patient has had one recurrence, there is a 16-25% chance of a second[2].

Survival Outcome

The most suggestive prognostic factors include staging, histology, number of involved surrounding structures, and completeness of tumor resection. An incomplete resection, the involvement of the great vessels and pericardium creates a higher recurrence and lower survival rate. In one study, patients with completely resected tumors have a 100% 5-year survival rate compared with 76% in those with incomplete resections. Those with pericardial involvement had a 71% survival rate compared to 98% in those without[9].

Summary

Clinicians should be aware of the risk of thymoma in patients presenting with MG even OMG. Imaging of the chest (e.g., CT) may disclose thymic abnormalities and referral to thoracic surgery is recommended for patients with possible thymoma. Surgical resection is the first line of therapy but depending on stage and extent of tumor additional multimodal therapy may be required.

References

  1. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations. J Clin Med. 2021 May 21;10(11):2235.
  2. 2.0 2.1 2.2 Venuta F, Rendina EA, Anile M, de Giacomo T, Vitolo D, Coloni GF. Thymoma and thymic carcinoma. Gen Thorac Cardiovasc Surg. 2012 Jan;60(1):1-12.
  3. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981 Dec 1;48(11):2485-92.
  4. Koga K, Matsuno Y, Noguchi M, Mukai K, Asamura H, Goya T, Shimosato Y. A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int. 1994 May;44(5):359-67.
  5. Yamakawa Y, Masaoka A, Hashimoto T, Niwa H, Mizuno T, Fujii Y, Nakahara K. A tentative tumor-node-metastasis classification of thymoma. Cancer. 1991 Nov 1;68(9):1984-7.
  6. Kirchner, T., Müller-Hermelink, H.K. (1989). New Approaches to the Diagnosis of Thymic Epithelial Tumors. In: Cecilia Fenoglio-Preiser, M., Wolff, M., Rilke, F. (eds) Progress in Surgical Pathology. Springer, Berlin, Heidelberg.
  7. Chen G, Marx A, Chen WH, Yong J, Puppe B, Stroebel P, Mueller-Hermelink HK. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer. 2002 Jul 15;95(2):420-9.
  8. Comacchio GM, Marulli G, Mammana M, Natale G, Schiavon M, Rea F. Surgical Decision Making: Thymoma and Myasthenia Gravis. Thorac Surg Clin. 2019 May;29(2):203-213.
  9. Chiappetta M, Aprile V, Lococo F, Zanfrini E, Nachira D, Meacci E, Korasidis S, Ambrogi M, Lucchi M, Margaritora S. Prognostic factors for survival in advanced thymomas: The role of the number of involved structures. J Surg Oncol. 2021 Oct;124(5):858-866.
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