Thymic Disorders - Clinical Implications & Management Principles.pptx

Concise presentation of basics of Thymic gland, pathologies, specifically thymomas, in relation to myasthenia gravis, and its management.

1. Thymic Disorders- Clinical Implications & Management Considerations Dr ROHAN REDDY C Dept of Thoracic Surgery MSMC, Narayana Health City

2. TOPICS OF DISCUSSION Thymus – the basics Spectrum of Thymic disorders & Clinical Implications Thymoma – Presentation, Classification, Clinical spectrum Surgery for Non-Thymomatous MG Surgery for Thymoma Adjuvant Modalities Rx for advanced cases

3. INTRODUCTION First being described as such by Galen of Pergamum (130 –200 AD) Etymology – Thymus from the Latin derivation “warty excrescence” Originally from Greek word - thymos , Meaning “soul” or “spirit,” as it was misrepresented as the seat of the soul by the ancient Greeks Thymus has remained an “organ of mystery” throughout the 2000-year history of medicine

4. ANATOMY One of the primary lymphoid organs. Encapsulated, soft, bilobed organ Two lobes joined in midline by connective Merges with the capsule of each lobe. Max size early part of life Particularly around puberty Persists actively into old age Considerable fibrofatty degeneration Hides existence of thymic tissue.

5. EMBRYOLOGY Arises bilaterally from the 3rd & 4th branchial pouches Elements from all 3 germinal layers Development - begins in 6th gest week. Migration - 8th week; leading to a fusion of the bilateral lobes Final position in the antero-superior mediastinum.

6. EMBRYOLOGY 9th gest week - purely epithelial. 10th wk - small lymphoid cells (fetal liver & BM; lobulation of gland. 14-16 wks – Diff into Cortex & Medulla Rapid growth thereafter Greatest weight before birth (≈15 g) Ectopic thymic tissue/ ectopic thymoma anywhere along this pathway.

7. ANATOMY Thymic lobes - loose fibrous connective tissue capsule Septa penetrate to the junction of the cortex & medulla Partially separate the irregular lobules Connective tissue septa - route of entry & exit for blood vessels and nerves Carry efferent lymphatics. Most migrant cells enter or leave the thymus by this route.

8. CORTEX Mainly - Lymphocytes, supported by network of finely-branched epithelial reticular cells. Rich Capillary plexus Superficial subcapsular cortex & Main cortex MEDULLA Network of reticular cells - coarser than in the cortex Lymphoid cells - relatively fewer Hassall’s corpuscles Fewer cells Central medulla of both thymic lobes - continuous from one lobule to the next.

9. HASSALL’S CORPUSCLES Characteristic finding in Thymus

10. EPITHELIAL FRAMEWORK Thymus – network of interconnected epithelial cells. Intercellular desmosomal attachments Appropriate microenvironment of cell–cell contact Release of paracrine factors Thymic lymphocytes (T cells) develop and mature. Vary in size & shape as per positions in the thymus. Subcapsular cells: Blood- Thymus Barrier Medullary epithelial cells tend to form more solid cords as well as thymic or Hassall’s corpuscles. Myoid cells – responsible for Autoimmunity in MG Several other cellular elements – connected to autoimmune process elaboration.

11. ASSOCIATED MEDICAL CONDITIONS MG affects – 1/3 rd – 1/2 of all thymoma patients, 10%–20% of myasthenia gravis patients have thymoma

12. ASSOCIATED MEDICAL CONDITIONS Response to stress: Atrophy; return to normal size; Rebound Hyperplasia Lymphoid Hyperplasia – Increase in lymphoid follicles; 65% association with MG

13. ASSOCIATED MEDICAL CONDITIONS Radiological differentiation thymic hyperplasia vs neoplasm – Important Diffuse symmetric enlargement of the gland ≈ hyperplasia, focal mass ≈ Neoplasm (thymoma) However, differentiation may be difficult on the basis of morphologic features alone. Several new imaging approaches - Chemical shift MR imaging Normal thymus vs Thymic hyperplasia - Latter demonstrates homogeneously decreased signal intensity on opposed-phase images May differentiate normal and hyperplastic thymus vs neoplastic involvement

14. THYMIC NEOPLASMS Thymic Epithelial Tumors: Thymoma Thymic Carcinoma Uncommon Thymic Neoplasms: Thymolipoma Thymic Carcinoid Lymphoma

15. CLASSIFICATION OF THYMIC EPITHELIAL TUMORS The WHO classification scheme correlates with invasiveness: Types A and AB are usually clinically benign and encapsulated (stage I) Type B has a greater likelihood of invasiveness (especially type B3) Type C is almost always invasive.

16. THYMIC NEOPLASMS Thymic Epithelial Tumors: Thymoma Thymic Carcinoma Uncommon Thymic Neoplasms: Thymolipoma Thymic Carcinoid Lymphoma

17. DIAGNOSTIC EVALUATION CT or MRI – most common modalities. Features assessed: Well-circumscribed or infiltration Signs of aggressiveness Infiltration into surrounding structure Atypical features – cystic areas, calcifications Important differentials: Retrosternal thyroid Lymphoma Germ cell tumor Several retrospective studies – Positive correlation of Invasive CT features with more aggressive histotypes

18. Size Lobulated Contour Infiltration Pulmonary Nodules

19. MRI in THYMOMA T1-weighted images: Signal intensity similar to muscle or normal thymic tissue T2-weighted images: heterogeneous

20. MRI in THYMOMA Useful in differentiating: Thymoma vs thymic cysts Latter demonstrates increased CT attenuation due to hemorrhage or high mucinous content. T2-weighted & contrast-enhanced MR: detects solid components of cystic lesions a finding that raises the possibility of cystic thymoma

21. PET SCAN Value of PET scan to predict Histology Hyperplasia vs tumour Thymoma vs thymic carcinoma, Thymoma subtype, or Invasiveness Debatable at best ( Kaira K et al. Ann Nucl Med 2011; 25: 247–253) PET – for subsequent follow-up of patients; to detect recurrences after first-line treatment (El- Bawab HY et al. Interact Cardiovasc Thorac Surg 2010; 11: 395–399)

22. DIAGNOSTIC EVALUATION Histopathological diagnosis - through - small biopsy – PARAMOUNT Generally, Anterior mediastinal Tumors- Percutaneous core needle biopsy Mediastinotomy Mini-thoracotomy [30]. FNA – Not recommended (cytological specimens of thymic tumours - hard to interpret) Pleural spaces should not be punctured to avoid tumour cell seeding. D/ ∆s thymic hyperplasia, other primary mediastinal malignancies - lymphoma or germ-cell tumours. lung cancer How to handle small biopsy specimens

23. MASAOKA - KOGA STAGING

24. MASAOKA - KOGA STAGING

25. MASAOKA - KOGA STAGING

26. SURGERY IN NON-THYMOMATOUS MG Thymectomy Trial in Non- thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX)

27. PRESENTATION CLINICAL EVALUATION There are 2 main scenarios that the surgeon may find himself to deal with: Patient referred to the surgeon for a mediastinal lesion Patient referred to the surgeon for MG

28. SCENARIO – 1: Pt presents with a mediastinal mass on routine imaging In the first case, a thorough evaluation of the patient’s medical history must be performed Assess Fluctuating muscle weakness Latent MG – protracted muscle weakness on NDMB (relaxants) Positive preop AChR level – risk of post-thymectomy MG – 1-3%; warrants thorough neurological assessment PRESENTATION

29. SCENARIO 2: Pt presents with a ∆s of MG Thorough clinical evaluation, serum Abs Chest imaging (CECT Chest) – to differentiate b/w thymic hyperplasia vs Early Thymoma Thymoma – definitve surgery; (Age < 60yrs) Thymic hyperplasia – Debatable options; based on the neurological disease Features on CT scan: Round/ oval shaped mass; moderately enhancing Size & extent of the disease Local invasiveness & ditant spread (including pleural/ pericardial implants) Presence of foci of calcification or necrosis PRESENTATION

30. PREOPERATIVE EVALUATION Anesthesiological assessment of patients with thymomatous MG is like that for patients with MG but without thymoma. Coexisting disease should be investigated carefully, particularly those that could affect MG, such as thyroid diseases. Particular details to pay attention surgical approach prolonged operative time possible resection of the surrounding structures (in case of thymoma)

31. Factors predicting Postoperative Myasthenic Crisis ( Leuzzi et al): Lung function assessment (FEV1, FVC) - most important parameters; in terms of pulmonary resection As a marker of disease control & postoperative crisis PREOPERATIVE EVALUATION

32. PRINCIPLES OF SURGERY The primary therapy depends on staging Thorough preoperative staging required

33. STRATEGIES IN THYMIC EPITH TUMORS Primary strategy: Upfront Surgery Vs No Surgery Complete resection represents the most significant and consistent prognostic factor on disease-free and overall survival Unfortunately, no clinical staging system reliably predicts resectability

34. STRATEGIES IN THYMIC EPITH TUMORS

35. SURGICAL PRINCIPLES Wide opening of the mediastinum and both pleural cavities - median sternotomy Generally, complete thymectomy, including the tumour, the residual thymus and perithymic fat, is preferred because local recurrences have been observed after partial thymectomy. The first step of the operation consists of a careful examination of the mediastinum and pleural cavities followed by evaluation of macroscopic capsular invasion, infiltration of peri-thymic and mediastinal fat, peritumoral and pleural adherences, and involvement of surrounding tissues. These findings, together with the sub-sequent pathological examination of the surgical specimen, constitute the basis of staging

36. SURGICAL PRINCIPLES If the tumour is invasive, en bloc removal of all affected structures, including lung parenchyma (usually through limited resection), great vessels, phrenic nerves and pleural implants, should be performed. Thoracotomy may be mandatory. Areas of uncertain margins are marked with clips to allow precise delivery of post-operative radiotherapy. Phrenic preservation may be balanced with complete resection in patients with severe myasthenia gravis. Frozen sections to assess tumour involvement of resection margins are not recommended, given the high risk of false negative results

37. SURGICAL ANATOMY Despite wide variability, the thymus is usually formed by 2 longitudinal spindles of capsulated tissue Fused in the middle - an asymmetric “H” 4 projecting extremities named “poles or horns”, similar to a butterfly , Lengths and sizes of the poles are variable (commonly Inf Rt horn-larger, Inf Lt – longer) Upper poles - thinner and reach the cervical area; lying deep to sternothyroid muscle

38. SURGICAL ANATOMY In tight proximity to the recurrent laryngeal nerves Anatomic limits: Anteriorly – sternum Posteriorly - pericardium, left innominate vein, trachea Laterally - Mediastinal pleura up to the phrenic nerves Cranially - cervical region up to the thyroid. Many anatomic variants are described The most frequent - Innominate vein running anteriorly along the left superior horn.

39. CONDUCT OF SURGERY - SURGICAL ANATOMY Arterial supply: Tiny and inconstant Originate from the Internal mammary & Inferior thyroid arteries. Venous drainage : Much more evident Takes place through 1 or 3 wide collectors Drain into inferior aspect of Innominate vein.

40. ECTOPIC SITES

41. CONDUCT OF SURGERY CLASSIFICATION Myasthenia Gravis Foundation of America (MGFA) Classification All resections are not equal in extent How much gross and microscopic thymus each technique is capable of removing Comparison of outcomes b/w different techniques Surgeon-dependant – experience, technique, patience, conviction & commitment Whether or not particular approach allows for total thymectomy when properly performed .

42. TYPES OF SURGERY Combined Transcervical and Transsternal Thymectomy (T-4) Extended Cervico -mediastinal thymectomy “Maximal” thymectomy Benchmark operation against which other resectional procedures should be measured These resections are exenteration in extent “Performed as if it were an en bloc dissection for a malignant tumor” Ensures no islands of thymus are left behind Guards against potential of seeding of thymus in the wound

43. TYPES OF SURGERY Combined Transcervical and Transsternal Thymectomy (T-4)

44. CONDUCT OF SURGERY Separate Cervical and thoracic incisions. Wide exposure of neck and mediastinum is obtained. A ‘T incision’ for large or malignant thymomas, reoperations, Obese with short neck pts. Mediastinal pleura incised bilaterally retrosternally From the level of the thoracic inlet to the diaphragm ( Arrows)

45. CONDUCT OF SURGERY Second mediastinal pleural incision (bilateral) Anterior to phrenic nerves. The posterior mediastinal pleura with adherent phrenic nerve (arrow) are elevated Teased off bilaterally underlying fatty thymic tissue.

46. CONDUCT OF SURGERY Sharp dissection on pericardium. En bloc resection from diaphragm to innominate vein From hilum to hilum, Including fatty thymic tissue in anterior pericardiophrenic fat "aortopulmonary window" (the left phrenic and vagus nerves are especially at risk here) aortocaval groove lappets of pericardium extending into the thymus both sheets of mediastinal pleura The innominate vein identified & thymus separated from it by dividing the thymic veins

47. CONDUCT OF SURGERY Cephalad to the innominate vein, the en bloc dissection is continued posterior to the strap muscles medial to the recurrent nerves anterior to the trachea terminated at the level of the thyroid isthmus Fibrous cords traced to their cephalad termination or into additional thymic lobes. Thyroid lobes mobilized; thymic tissue is searched for behind and superior to the thyroid gland. On anatomical basis – any procedure less comprehensive - likely to be incomplete.

48. TYPES OF SURGERY Standard Transsternal Thymectomy (T-3a) Standard transsternal thymectomy used by the pioneers Blalock (Followed by Keynes, Clagett ) Originally limited to - Removal of the well-defined cervical-mediastinal lobes Thought to be the entire gland Falls short of total thymectomy; residual thymus found in neck & mediastinum at reoperation Considered Incomplete ; no longer in use for Rx of MG Alfred Blalock Smoking did Kill him!

49. TYPES OF SURGERY Extended Transsternal Thymectomy (T-3b) Aggressive transsternal thymectomy Transsternal Radical thymectomy (Championed by Masaoka, Mulder etc) Similar to the Maximal-T4 technique; extent of resection varies Cervical thymic extensions are removed from below +/- some additional cervical tissue NO formal neck dissection. Disadvantages - removes less tissue in the neck (30% ectopic) Mulder - risk RLN injury while extensive neck dissection of maximal-T4 approach not “justified by the small potential gain” Akira Masaoka (1930-2014)

50. TYPES OF SURGERY Transcervical Thymectomies (T-1) Basic Transcervical Thymectomy (T-1a) Extended Transcervical Thymectomy (T-1b) Extended Transcervical Thymectomy Variations (T-1c-d)

51. CONDUCT OF SURGERY Transcervical route - can be considered the very first real minimally invasive approach.

52. TYPES OF SURGERY Transcervical Thymectomies (T-1) Basic Transcervical Thymectomy (T-1a): Employs intracapsular extraction of the mediastinal thymus Small cervical incision Limited to removal of intracapsular portion of the central cervical-mediastinal lobes. No other tissue is removed in neck or mediastinum Although considered “total”, unequivocally an incomplete resection In both the neck and the mediastinum Evidenced by findings of residual thymus during reoperations

53. TYPES OF SURGERY Transcervical Thymectomies (T-1) Extended Transcervical Thymectomy (T-1b) : Employs special manubrial retractor - Improved exposure via cervical incision Mediastinal dissection is extracapsular; includes resection of visible mediastinal thymus & fat Sharp dissection on pericardium +/- ; Inclusion of mediastinal pleural sheets +/- (less often) Dissections vary in extent; exploration and removal may exceed limits of cervical-mediastinal extensions Cooper – “when performed by others may be less extensive than the procedure performed by us!”

54. TYPES OF SURGERY Transcervical Thymectomies (T-1) Extended Transcervical Thymectomy Variations (T-1c-d): Partial median sternotomy (T-1c) Use of Videoscopic technology (T-1d) Aids in visualization and dissection of the mediastinum. Video-assisted variations include addition of transcervical thoracoscopy or subxiphoid videoscopic inferior approach

55. TYPES OF SURGERY Videoscopic-Assisted Thymectomies (T-2) Classic VATS (Unilateral) (T-2a) Video-Assisted Thoracoscopic Extended Thymectomy (Bilateral with Cervical Incision) (T-2b) Bilateral VATS (No Cervical Incision) (T-2c)

56. TYPES OF SURGERY Videoscopic-Assisted Thymectomies (T-2) Classic VATS (Unilateral) (T-2a): Complete removal of grossly identifiable thymus variable amounts of anterior mediastinal fat diaphragmatic fat, including, Cervical extensions Since unilateral - contralateral side of mediastinum is not well visualized

57. TYPES OF SURGERY Videoscopic-Assisted Thymectomies (T-2) Video-Assisted Thoracoscopic Extended Thymectomy (Bilateral with Cervical Incision) (T-2b): The video-assisted thoracoscopic extended thymectomy (VATET) Bilateral thoracoscopic exposure - improved visualization of both sides A possible cervical incision - exposure of RLN & removal of cervical thymic lobes + pretracheal fat under direct vision Extensive removal of the mediastinal thymus and perithymic fat is described Modifications to VATET include - addition of an anterior chest wall-lifting method Conceptually more complete than the unilateral VATS - Offers excellent visualization of both sides & includes a neck dissection as well

58. TYPES OF SURGERY Videoscopic-Assisted Thymectomies (T-2) Bilateral VATS (No Cervical Incision) (T-2c): Similar resection capability to extended transsternal thymectomies (T-3b) Studies – 2-3% of thymic tissue may be left in the absence of additional cervical approach Some authors prefer to refer it as VATET

59. CONDUCT OF SURGERY - VATS The thymus gland – approx. located in midline of anterosuperior mediastinum; lobulated, including fat and glandular tissue. ‘Grey-ink’ colour (variable); within the diffuse yellow of mediastinal fat. Initial view from the Left port. Initial view from the Right port.

60. CONDUCT OF SURGERY – VATS Classic VATS (Unilateral) (T-2a) The thymus gland – approx. located in midline of the anterosuperior mediastinum. Adults - appears as a lobulated structure, including fat and glandular tissue. The ‘grey-ink’ colour (variable) identifies the thymus in the diffuse yellow of mediastinal fat. Initial view from the Left port.

61. CONDUCT OF SURGERY - VATS Goal of a successful thymectomy for MG – “Remove as much thymic tissue as possible” Must know all the sites of thymic distribution within the mediastinum View from the Left port. View from the Right port.

62. Rückert JC et al , The Annals of Thoracic Surgery, 2000, Vol.70,Iss.5:1656-61 Thorascopic thymectomy ( tThx ) > Transternal thymectomy ( sThx ): Vital capacity Forced Vital capacity Forced Expratory Volume in 1 st sec Peak Expiratory Flow TYPES OF SURGERY Videoscopic with Robotic Technology (U/L or B/L) (T-2d)

63. Evidence for MIT Skepticism towards MIT w.r.t oncologocal results in early years Debunked by several workers

64. TYPES OF SURGERY Videoscopic with Robotic Technology (U/L or B/L) (T-2d) Introduction in the early 2000s Becoming increasingly common since then Advantages: The instrumentation offers Enhanced optics with three-dimensional visualization 12x magnification Surgical arms allows precise tissue dissection. Extensive, yet, safe resection of the thymus + anterior mediastinal fat + neck exploration Disadvantages: significant cost and time to the procedure.

65. CONDUCT OF SURGERY Patient placed to the left edge of the table with the left arm placed parallel to the table. The prepped, sterilized and draped operative field. Skin marks for three trocars. Port placements.

66. CONDUCT OF SURGERY Resection starts in the middle of the pericardium and moves cranially along the nerve.

67. CONDUCT OF SURGERY The incision proceeds to the right side until the right lung is visible, but the right pleural cavity is still closed

68. CONDUCT OF SURGERY Management of the upper poles and thymic veins.

69. CONDUCT OF SURGERY The incision proceeds to the right side until the right lung is visible but the right pleural cavity is still closed

70. TYPES OF SURGERY Videoscopic with Robotic Technology (U/L or B/L) (T-2d) Technical Tips: Patient positioning . To get enough space for movement of the instruments, Patient should be placed supine With the body moved to the left edge of the operating table Lowering the left arm to be parallel to the table Placing the right one naturally along the body Trocar placement . Some surgeons prefer the right-sided approach - Due to concerns of pericardial injury/ heart, while inserting the trocars through the left side Following 12-mm camera trocar, insufflation with CO2 to a pressure of 8 mmHg - Enlarges the retrosternal space, facilitates insertion of the other trocars under vision. For the inexperienced, spatula used to push the heart aside, or lightly lifting the camera - effective to acquire adequate space and ensure the safe placement of the trocars.

71. TYPES OF SURGERY Videoscopic with Robotic Technology (U/L or B/L) (T-2d) Technical Tips: Thymic upper pole resection . Bringing them down by constant retraction before resection - effective way to manage the upper poles Thymic vein management . Usually, 2-3 thymic veins running about 2 cm before draining into the left innominate vein Therefore, special attention should be paid to identify the left innominate vein Avoid injury to thymic veins and the innominate vein The left innominate/superior vena cava angle is a common site for a thymic vein Also, common anatomic variations occur at the upper left horn and run behind the innominate vein, Easy to handle through the left-sided approach.

72. TYPES OF SURGERY Videoscopic with Robotic Technology (U/L or B/L) (T-2d) Major Disadvantages: Increased procedural (docking) time High cost Emergencies - such as major bleeding, requiring open conversion, The undocking of the robotic system and sterilization of the operator Consume much valuable time Possibly resulting in the situation being more difficult to manage

73. TYPES OF SURGERY Infrasternal Thymectomies (T-5) Subxiphoid incision, reportedly improved visualization and dissection of bilateral mediastinal spaces otherwise, difficult from a unilateral thoracoscopic approach Aesthetically more appealing results, Modifications: Bilateral thoracoscopic ports Cervical incision - to facilitate neck dissection; combined transcervical- subxiphoid thymectomy (T-5a) utilizes both an open cervical dissection and subxiphoid video- assisted inferior approach comparable resection to the “maximal” T-4 approach [64]. Disadvantages: decreased manoeuvrability - increases operative time or hamper adequate dissection Robotic technology - overcomes these limitations in dexterity

74. TYPES OF SURGERY Infrasternal Thymectomies (T-5) Subxiphoid Robotic-assisted Thymectomy

75. LYMPH NODE METASTASES Incidence of LN Mets - largely undetermined in thymic epithelial tumours Literature unclear - how often nodes are biopsied or examined Landmark Japanese series (1320 resected thymic tumours) : lymph node invasion - mostly located in the anterior mediastinum and found in 2% of thymomas, 1% of stage I cases, 6% of stage III cases Nodal invasion higher in thymic carcinomas - anterior mediastinum (70%), other intrathoracic locations (35%), and extrathoracic sites (30%)

76. lymph node metastases Unfavourable prognostic value – only for carcinomas Any suspicious nodes (enlarged, firm or hypermetabolic at PET- scan) should be removed and separately labelled and submitted. Routine removal of anterior mediastinal nodes – for stage III–IV thymomas For thymic carcinoma - even more extensive nodal dissection (anterior mediastinal, intrathoracic, supraclavicular and lower cervical areas) LYMPH NODE METASTASES

77. ADJACENT STRUCTURE INVASION Intraop detection of Phrenic N. involvement: Special concern in Myasthenoc pt PN-spearing Sx (when involved with tumor): No differenve in DFS or OS Recurrence rates were higher 5% of permanent postop diaphragmatic palsy 15% of resected PN – didn’t show tumor infiltration Bilateral PN involvement: Mandatory to spare one of them – address with definitive RT Concomitant Pulmonary resections: Increased risk of BPF (in pts on steroids)

78. SURGICAL PRINCIPLES Appropriate selection of patients for a MIT : location - in the anterior mediastinum tumor encapsulation distinct fat plane between tumor & vital organs existence of residual (normal) appearing thymic tissue no mass/compression effect unilateral tumor predominance tumor dimension - lesions <3 cm ( tumors from 5-10 cm have also been resected ) Most important of all - oncological & technical safety & completeness

79. SURGICAL PRINCIPLES The choice for MIT should not alter principles of complete resection: resection of the tumour, the thymus and the mediastinal fat; dissection and visualisation of the innominate vein and both phrenic nerves; sufficiently large access incision to prevent specimen disruption; use of a retrieval bag; and exploration of the pleura. Conversion to open surgery is mandatory if required to achieve complete resection Should NOT be considered a complication of the minimal approach.

80. SURGICAL PATHOLOGY RECOMMENDATIONS Communication between surgeons and pathologists is crucial while sending the specimen Responsibility of the operating surgeon Proper orientation of the specimen Designation of involved structures, organs or areas of concern Mediastinal board: consisting of a line diagram of the mediastinum placed on a simple cork or wax board.

81. SURGICAL PATHOLOGY RECOMMENDATIONS

82. SURGICAL PATHOLOGY RECOMMENDATIONS The operative note should mention the following elements: whether gross tumour was left behind and, if so, location of residual tumour; extent of resection performed; presence and location of any adhesions that were simply divided (not suspicious for involvement); any additional structures or organs removed; any sites of intra-operative concern, how these were marked on the specimen and in the patient; which nodal areas were explored and the extent of assessment; and the presence or absence of pleural and pericardial lesion. SURGICAL PATHOLOGY RECOMMENDATIONS

83. RADIOTHERAPY PRINCIPLES

84. ADVANCED TUMORS

85. UNRESECTABLE TUMORS

86. SUMMARY

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