SURGICAL DISORDER OF THE THYMUS AND MYASTHENIA GRAVIS.pptx

Thymus

1. SURGICAL DISORDER OF THE THYMUS AND MYASTHENIA GRAVIS PRESENTER; DR. FRANK PATRICK FACILITATOR; DR. MUJUNI/RAMADHANI

2. Outline Anatomical relation Epidemiology Disorder of thymus Management of thymus disorder Myasthenia gravis Case study

3. Anatomy of the thymus gland

4. Anatomy Thymus is asymmetrical bi-lobed structure located just posterior to the manubrium. Superiorly can reach up to the thyroid gland and inferior can reach up to the pericardial sac in the anterior mediastinum. It is larger structure in children and begin to atrophy after puberty. In elderly it is barely identifiable as an organ, and it is replaced by fatty tissue

5. Anatomy Blood supplied artery from internal thoracic artery venous drainage is by left brachiocephalic and internal thoracic veins Lymphatic drainage involve the following Along the internal thoracic artery (parasternal) At the trachea bifurcation(tracheobronchial) In the root of the neck

6. Surgical disorder of the thymus Thymic masses can be any of the following: Thymoma Thymic carcinoma Thymic carcinoids Thymolipomas Thymic cyst

7. THYMOMA Derived from Thymic epithelia cells. Traditional histological classification. Predominantly lymphocytes Predominantly epithelia Mixed; accounts for more than 50% Spindle-cell variant: subtype of epithelia predominant Thymoma, found to have relatively better prognosis.

8. Thymoma Thymoma are 95% to 100% positive for cytokeratin immunohistochemistry, this feature distinguish it from lymphoma. Chromogranin staining is negative for Thymoma. Distinguish Thymoma from Thymic carcinoid which is positive 40% to 70% of the Thymoma are encapsulated the rest form grossly invasive lesion. Distant metastasis in Thymoma are rare(<5%)

9. Epidemiology Most common Thymic tumor t ypically occur in adults aged 40 to 70 years rare in children and adolescents. Male and female are equally affected Etiology is unknown Alcohol, tobacco smoking and ionizing radiation do not appear to be risk factor for Thymoma . O ften have other autoimmune diseases. Approximately 30% to 50% have myasthenia gravis

10. Staging and classification of Thymoma WHO classification Masaoka and colleague AJCC TNM staging

11. WHO histological classification

12. Masaoka and colleague

13. Combine WHO & Masaoka staging

14. AJCC TNM staging 8 th edition

15. Clinical presentation More than 20% of the patient are asymptomatic 25% to 30% of patient have symptoms related to compression of adjacent mediastinal structure; Coughing Chest pain Shortness of breath Symptoms related to associated conditions such as Myasthenia gravis, endocrine disorder and hypogammaglobinemia.

16. Prognosis Of Thymoma STAGE (Masaoka staging) 5-year survival rate 10-year survival rate I 90% 80% II 90% 80% III 60% 30% IV Less than 25% N/A Blumberg D et al 1993

17. Systemic disease associated with Thymoma. Myasthenia gravis Cytopenias (most commonly, red cell hypoplasia) Nonthymic malignancies Hypogammaglobulinemia Systemic lupus erythematosus Polymyositis Rheumatoid arthritis Thyroiditis Sjögren’s syndrome Ulcerative colitis

18. Investigation for Thymoma Imaging Plain radiograph both PA and lateral view CT scan PET/CT-scan MRI

19. Imaging

20. Lab tests serum Alpha fetoprotein Beta-human chorionic gonadotrophin hormone Lactate dehydrogenase Biopsy Needle biopsy Anterior mediastinotomy (Chamberlain procedure) Trans cervical mediastinotomy VATS

21. Thymic Carcinoma Aggressive and rare Thymic tumor. They usually larger, firm, infiltrating with frequent cystic change and necrosis. Encapsulated in 15% or less of cases. Distinguished from Thymoma by; Malignant histological feature Immunohistochemical characteristics Genetic features Paraneoplastic syndrome including myasthenia gravis is rare in Thymic carcinoma unlike Thymoma. It occur in wide range of age including adolescence unlike Thymoma which commonly occur in adult

22. WHO histological subtype of Thymic carcinoma Squamous cell carcinoma Salivary gland-like carcinoma Squamous cell carcinoma NOS Mucoepidermoid carcinoma Basaloid carcinoma Clear cell carcinoma Lymph epithelial carcinoma Sarcomatoid carcinoma Adenocarcinoma Carcinosarcoma Adenocarcinoma NOS Adenocarcinoma enteric type Low grade papillary adenocarcinoma Thymic carcinoma with adenoid cystic carcinoma-like features Adenosquamous carcinoma NUT carcinomas Carcinoma undifferentiated NOS Thymic carcinoma NOS

23. Thymolipomas Located within the Thymic capsule in contrast to other mediastinal lipoma Contain mature adipose cells as well as normal Thymic tissues Associated with paraneoplastic syndrome such as red cell aplasia, aplastic anemia and Hypogammaglobulinemia Treatment is by Thymolipomas excision

24. Thymic cyst Account to 0.2% of anterior mediastinal mass They are asymptomatic and discovered accidentally To confirm the diagnosis they must contain Thymic tissue within the cystic wall They are completely benign Removal is indicated to rule out other entity such as Thymoma with cystic component

25. Management- initial management in patient with Thymic tumor

26. Management- post op management

27. Management- local advanced, advanced or recurrent disease

28. Myasthenia gravis Most common disorder of neuromuscular transmission It is an autoimmune disorder Annual incidence in Tanzania is 3 per 1000000 Female incidence peak in 3 rd decade of life while male in 6 th to 7 th decade

29. Myasthenia gravis Two clinical from exists, namely Ocular myasthenia gravis Generalized disease

30. Pathophysiology Acetylcholine receptor autoantibodies (90%) Muscle specific kinase antibodies Seronegative myasthenia gravis Thymus hyperplasia and Thymoma Genetic factors

31. Acetylcholine receptor antibodies Dysfunction of AchR occur due to the following mechanism Blocking Ach binding to the AchR Cross-linking and internalize AchRs Activating compliment mediated AchR destruction. decrease in number of AchR overtime Decreases transmission of action potential along the neuromuscular junction.

32. Muscle specific kinase antibodies Muscle specific kinase (Musk) It is a transmembrane component of the postsynaptic neuromuscular junction. It mediated clustering of AchR in postsynaptic membrane. Other proteins involve in this AchR clustering Agrin Lipoprotein-related protein 4 Adaptor protein Dok7 Disruption of Musk eventually reduce transmission along the neuromuscular junction.

33. MusK function

34. Thymus hyperplasia and Thymoma Among AchR-positive Myasthenia gravis 60 to 70% have hyperplasia of the thymus 10 to 12% have Thymoma Disease often improve or disappear after thymectomy Factors that facilitate the formation of anti -AchR Expression of Acetylcholine receptor on myoid cells in the thymus Abnormal antigen presentation via MHC-II with overexpression of cathepsin V

35. Seronegative myasthenia gravis Tested negative for anti-AchR with standard immune assay. If anti- MuSK is also negative it is termed as double seronegative. Associated by the presence of low affinity AchR antibody which can not be detected by the standard Anti-AchR assay. Low affinity anti-AchR can activate compliment in the same manner as anti-AchR

36. Role of genetic Certain human leukocytic antigen have been associated with MG namely; HLA B8, DRw3, DQw2 MuSK antibody positive myasthenia is associated with haplotypes DR14 and DQ5. Patient with MG frequently have immuno-mediated disease and family history of autoimmune disorders.

37. Transient neonatal MG Occur in infant whose mother has myasthenia gravis Anti-AchR crosses the placental barrier Most infant posses anti-AchR but only10-20% develop neonatal MG Alpha fetoprotein inhibit the binding of anti-AchR to AchR Lower maternal Anti-AchR by means of plasmapheresis reduces morbidity

38. Congenital myasthenia gravis Mother is unaffected No antibody activities Pathophysiology involves Abnormal gene mutation of presynaptic nerve terminal resulting in impair release of Ach Congenital lack of cholinesterase AchE Impair capacity of Ach receptor to interact with Ach Abnormal low number of AchR

39. Myasthenia crisis Defined as worsening of myasthenia gravis muscle weakness requiring intubation and non-invasive ventilation. Precipitants; Concurrent infection Surgical intervention Pregnancy Childbirth Tapering of immunotherapy medication Can also occurs as a natural history of myasthenia gravis

40. Cholinergic crisis Overstimulation at NMJ of muscarinic or nicotinic receptor to excess Ach Excess Ach can be due to inactivity/inhibition of acetylcholinesterase Can occur in MG patient who take too high dose of cholinesterase inhibitor The chemical sarin or nerve gas, it inhibit cholinesterase Also high dose of cholinesterase taken to reverses muscle paralysis during GA

41. Myasthenia and Cholinergic crisis. Tensilon test used to differentiate the two Symptoms improve in myasthenia crisis and worsening in cholinergic crisis. Tensilon also known as edrophonium, is cholinesterase inhibitor. Upon administration it increase concentration of Ach in the NMJ Increases Ach-AchR binding in myasthenia crisis which improves symptoms

42. Symptoms of myasthenia gravis Ocular (50%) Eyelid dropping-curtain sign Double vision Generalized Bulbar(15%); difficult in swallowing, slow and slurred speech, hypotonia, nasal regurgitation, fatigue chewing Facial; weakness of facial expression ( M yasthenic sneer) Dropped neck syndrome Proximal muscle weakness Rarely difficult in breathing

43. Investigation; Lab workup Anti- MuSK Ant-AchR Anti- stiated muscle antibody Antistriational antibody

44. Investigation; Electrophysiological studies Repetitive nerve stimulation study Single fiber electromyography Imaging X-ray CT scan MRI

45. DDX Thyroid ophthalmopathy Brainstem and motor cranial nerve pathology Generalized fatigue Lambert-Eaton Myasthenic syndrome Botulism Dermatomyositis

46. Treatment Symptomatic (anti-cholinesterase agent) Neostigmine and pyridostigmine Chronic immunomodulating treatment Prednisolone, cyclosporine and azathioprine Rapid immunomodulating treatments Plasmapheresis and iv immune globulin Surgical treatment (thymectomy)

47. Case 1- (S.dahal et al 2019) 45y female from Nepal presented with progressive dysphagia, currently able to swallow liquid for 7 months, difficult in breathing for 2 months, upper limb weakness more on the evening. No decreased in appetite, weight loss or coughing. How do you investigate??

48. Imaging Antibody test for MG was 8.67mmol/L positive

49. Done Medical management for one month (pyridostigmine 60mg) Surgical management Trans sternal thymectomy (clamshell incision) 12 by 13 cm mass exposed Single lymph node originating from the internal mammary artery identified Histopathology showed Thymoma WHO stage B2

50. danke

51. Reference