Mesothelioma Questions
IHC Mesothelioma
- DDX from adeno (primary lung or metastatic) - No single marker is sufficient: Requires panel Positive for Mesothelioma: - Calretinin - WT1, EMA - CK 5/6 Negative: - CEA, TTF1 (positive in adeno) Electron microscopy: - Mesothelioma: long microvilli - Adenocarcinomas: short
Discuss the place of radiation therapy in the adjuvant setting, following extrapleural pneumonectomy (EPP)
- No randomised data - IMRT or VMAT increase conformality and consistency in delivery but increased dose to the contralateral lung and heart Pros: - Better local control vs surgery alone - Retrospective serie (Ohri): Better survival rate with RT and surgery (40% increase) vs Rt alone (20% increase) vs Surgery alone (25%) Cons: - Local recurrence remains high at 50% - Steep learning curve - Risk of fatal pneumonitis up to 10% Dose: 54Gy in 30# - 30-40 Gy: entire hemithorax (1.8-2 Gy per #) - Boost to high-risk regions: 50-60 Gy Typical protocols: 1) Neoadjuvant chemo → EPP → hemithoracic RT 2) EPP → Chemo → hemithorax RT
Extrapleural pneumonectomy
- Radical procedure - Resection: lung, pleura, MN nodes, pericardium, ipsilateral diaphragm - Aims: cytoreduction and good palliation - No evidence that improves survival - High postop morbidity - Mortality 4-31%, MS 4-20 mo Candidates: - Negative mediastinoscopy/laparoscopy - Good cardiac function - Predicted postop FEV1 of 0.8L Morbidity: - Arrhythmia (reversible AF 44%) - Infections: Empyema, pneumonia, epicarditis - TE - GI complications
Describe the indications for, and surgical techniques of: Pleurodesis
- Significant pleural effusion - Fusion of two sides of pleura with talc
Describe the indications for, and surgical techniques of: Pleurectomy
- Stripping of entire pleural surface (decortication) - Preserve lung parenchyma - R0 is impossible in most cases - PORT fields & doses are limited due lung - Successful at treating pleural effusions but does not ↑ OS and no long term survivors - Majority pts with LR - MS is 7-21 mos, periop mortality 2-5% Candidates: - Good PS, young age - Early stages - Surgeon experience - Medically unfit, CV risk (Not tolerant for EPP) PD vs EPP: - Operative mortality greater for EPP (7 vs 4%) - EPP was associated with a worse OS (median 12 vs 16 months) but no difference stage by stage → OS PD is comparable to EPP
Changing patterns of disease relapse with improved local treatment
A) After EPP: - Local disease failure still a considerable clinical problem following complete EPP (50%) - Pts with epithelial histology and receiving adjuvant RT were associated with an improved disease control B) After trimodality therapy - DM were the most common form of relapse: peritoneum, contralateral pleura, and contralateral lung - Locoregional recurrence decreased to 13-20% (MD Anderson) - 5% patients with recurrence at the margins of RT site Role of RT: - Improves LC - Don't improve OS
A 35 year old man is found to have a large mediastinal mass. He has no history of malignancy and imaging work-up reveals no other sites of disease. List the potential biopsy methods for this patient and discuss the advantages and (2) disadvantages of each. Indicate your preferred method for this situation.
A) CT guided core biopsy Pros: - Low morbidity rate - Does not require general anaesthesia - Minimally invasive - Good diagnostic yield - Relatively cheap and available Cons: - Bleeding and pneumothorax - Radiation exposure B) Endobronchial Ultrasound (EBUS) core Bx Pros: - Allows assessment of airways, biopsy and washings - Shorter procedure vs mediastinoscopy - Sensitivity comparable to mediastinoscopy - Cost saving - Minimally invasive Cons: - Not widely available - Inferior NPV vs mediastinoscopy C) Mediastinoscopy or open lung biopsy - Highest diagnostic yield Cons: - Invasive, high cost - High morbidity - Requires GA I would choose EBUS if available - Less invasive - Good diagnostic yield - Less complications vs CT guided
If this situation of uncertainty arises, what should the oncologist discuss with (3) the pathologist?
A) Clinical context of the patient (Risk factors, patient wishes, radiological appearances and intraoperative findings.) B) Information of location and orientation of specimens, and areas of particular concern C) Provision of clinical photographs D) Details of previous treatments (Radiotherapy, surgery, chemotherapy)
Discuss the place of radiation therapy in the definitive management of mesothelioma
A) Definitive: - Good PS, young - Difficult to deliver high dose RT to all pleural surfaces without unacceptable toxicities - Retrospective series showed that RT (45-60 Gy) can improve patient survival by about 20% (although 40% received chemo and 20% surgery) Palliation - Unresectable pts - Useful for local symptoms with high response rates with 30Gy/10# (reasonably radiosensitive)
Subtypes, classification and immunohistochemistry
A) Epitheloid (50%) - Best prognosis - Resembles adenocarcinoma (cuboidal/columnar cells, papillary structure) - Numerous & long surface microvilli - Usually more uniform, cuboidal, & less crowded B) Sarcomatous or mesenchymal (20%) - Less common - WORSE prognosis - Malignant spindle cells (like sarcoma) C) Mixed or biphasic (30%) - Has both components
List the technical factors regarding the specimen that might prevent the pathologist (3) from establishing a firm diagnosis.
A) Inadequate material: - Tissue sampling not representative of the lesion - Insufficient tissue (Lack of architectural information, not enough tissue for IHC) - Lack of communication with radiologist/Surgeon B) Inadequate processing of tissue - Inadequate sections, fixation, stains, ancillary test - Deterioration of specimen
Investigation and Evaluation
A) Patient history & PE: - PS/comorbidities/occupational Hx - Smoking status - Symptoms onset/severity B) Labs: - FBC, MBA20 (including renal function) C) Imaging: - Staging with CT scan thorax, abdomen - Consider MRI if potentially resectable D) Tissue: - Cytology analysis with electron microscopy and IHC - if equivocal, CT guided biopsy or VATS E) Other: - Lung Function Tests - Consider bronchoscopy and Dx laparoscopy
c) What are the management options for mesothelioma confined to the right hemithorax? Discuss the advantages and disadvantages of each option. (5 marks)
A) Pleurodesis - Palliative procedure - Pleural effusion most common symptom. B) Radical pleurectomy and decortication (P/D) - Excision of entire parietal and visceral pleura - Preserves lung Pros: - Successful treating pleural effusions - Better quality of life than EPP and comparable survival - Lung sparing Cons: - No long term survivors - Higher risk of recurrence C) Extra-pleural Pneumonectomy (EPP): - Involves resecting lung and pleura Pros: - Better chance of removing all cancer (Aims at cytoreduction) - Less risk of local recurrence - Standardised procedure Cons: - Radical procedure - No evidence that improves survival - High post-op morbidity C) Trimodality Therapy: Surgery → Chemo (cisp/adria/cyclo) & PORT (54Gy/30#) Pro: - Long term survival reported in highly selected pts Cons: - Local recurrence remains high at 50% - Morbidity
In a patient who presented with pleural effusion and pleural-based nodules. You suspect malignancy. List the methods that can be used to obtain a tissue diagnosis and describe (3) the advantages and disadvantages of each method.
A) Thoracentesis (Pleural tap) Pros: - Less invasive procedure, relatively easy to perform - Can be used as a palliative procedure - Can help to DDx from adenocarcinoma (electron microscopy and IHC) - Relatively cheap and accessible Cons: - Often equivocal (inability to distinguish tumor cells from reactive mesothelial cells). Sensitivity <40% - Can't diagnose mesothelioma on FNA - Biopsy is required for medicolegally reasons - Risk of pneumothorax, haemorrhage B) CT guided core Pros: - Better sensitivity than pleural tap (>80%) - Relatively cheap and accessible - Patient sedation is not usually required and the procedure is well tolerated Cons: - Radiation exposure - No therapeutic benefit - Breath-hold requirement - Complication rates up to 10% (pneumothorax) C) VATS (video-assisted thorascopic surgery) Pros: - Better visualization - Diagnostic yield of 90-95% - Effectively drains all fluid Cons: - Invasive procedure, requires a general anaesthetic - Major complications up to 15% of cases
Chemo
A) Unresectable disease: Cisplatin + Pemetrexed!! EMPHACIS Study (Vogelzang, 2003) - Unresectable mesothelioma (A) Cisplatin vs (B) Cisplatin + pemetrexed (Alimta) Results: - Better RR (17 vs 41%) - Better MS (9 vs 12 mos) ---------------------------------------- EORTC/NCIC (Van Meerbeecz, 2005) - Compared Cis ± Raltitrexed (Tomudex) in 250pts Results: - Combo improved MS (8.8a vs 11.4 months, NS)
Utility of surveillance imaging in the at-risk group
A) Workers exposed to asbestos: - Baseline lung function tests B) High risk of asbestos related disease - Chest x-ray at 3-5 year intervals → Early - May be followed-up with High Resolution CT if results are unclear If calculated risk of developing lung cancer exceeds 1.34% over 6 years from *any combination of risk factors and asbestos exposure* - Individual can be screened using annual Low-dose Computer Tomography for lung cancer C) Non-occupational exposure to asbestos: - Not been as well investigated and guidelines are not as clear
A 70 year old man with a history of occupational asbestos exposure presents with a large right pleural effusion. Pleural fluid cytology shows malignant cells. a) How would you further evaluate this patient to confirm a diagnosis of mesothelioma? (2 marks)
Acute management: - ABCD approach to ensure airway and patient safety - Analgesia A) Patient history & PE: - PS/comorbidities - Symptoms onset/severity/management - Occupational exposure: asbestos (given), RT B) Labs: - FBC, EUC, LFTs C) Imaging: - Staging with CT scan thorax, abdomen - Consider MRI thorax if potentially resectable D) Tissue: - CT guided biopsy or VATS - Cytology analysis with electron microscopy and IHC E) Other: - Lung Function Tests - Consider bronchoscopy and Dx laparoscopy
The importance of asbestos in aetiology
Asbestos: - 80% cases (Life time risk is 10%) - Long latency: 20-40 yrs - Occupational exposure: Building, shipping, insulation, car brakes - May be partners (or children) of people working in these industries (very low exposure) - Crocidolite fibre: most carcinogenic - Incidence still rising, expected to peak 2020 - M>F, 50-70s 4 mechanism: - Pleural irritation - Interference with mitosis (mitotic spindle) - Oxygen radicals - Persistent kinase-mediated signals
The patient undergoes surgery and the surgeon reports that he has left macroscopic disease at the level of the aortic arch. Describe a suitable radiation therapy technique and dose fractionation (3) schedule for this patient.
Course of adjuvant RT with curative intent - 60 Gy/30#, 9#s fortnightly - IMRT technique, prescribed to PTV as per ICRU 83 - DIBH technique 3D:- AP/PA + ant obliques- Ant wedged pair. Sim: - Supine position, arms up - Vac Bag for immobilization - 3DCT, 2 mm per slice, including all lung volume. Fusion Target Volumes: - GTV: Gross tumour volume - CTV: GTV + 1 cm + Surgical bed - ENI not recommended - PTV: CTV + 1 cm OAR: - Spinal cord: ≤45 Gy - Heart: V40 <50% (V40 <40% if CRT), V50<40 - Lung: V20<30, V30<20 - Esophagus: V60<30, V55<60, V45<100
Even if a technically good specimen (with adequate tissue) is provided to the pathologist, a firm diagnosis is not always made. What interpretive factors might prevent the pathologist from confidently (2) determining if the pathological features are consistent with a malignant or benign process, and, if a malignant process is diagnosed, the exact type of malignancy?
Diagnostic misinterpretation - Inadequate access clinical information (i.e. Details of lesion location and orientation) - Insufficient experience - False positive/negative - Misclassification: grade, margins - Distinction between primary and secondary tumours
A diagnosis of mesothelioma is confirmed. b) Describe the factors which influence management options in this man. (2 marks)
EORTC index: Patient factors: - Poor PS/comorbidities - Age (>65) - Male - High WBC count - Chest pain at dx - Lung reserve Tumour factors: - Sarcomatous subtype - Stage C) Treatment factors: - Resectability - Experience of their surgeon - Certainty of the Dx
History, Physical Examination
History - Occupational history (including family exposure) - Habits: Smoking Usually gradual onset/nonspecific symptoms: - Chest pain (usually non-pleuritic) MC - Dyspnea (pleural effusion) MC - Cough - Hoarseness, Dysphagia - Fatigue, WL, Night sweats: months prior - DM: Bone, liver, or CNS Acute symptoms of local invasion (Rare): - Brachial plexus - Compression of the spinal cord - SBO (abdominal pain, distension, and vomiting) - SVC Sd: Head fullness or facial swelling - Cardiac involvement: Arrhythmias or heart failure. Rx: - Recurrent pleural effusion - Pleural thickening found incidentally on CXR
What are the medicolegal implications of establishing a diagnosis of mesothelioma? (1 mark)
Implications: - Usually occupational exposure - Long latency: 20-40 yrs - Partners of people exposed with asbestos might be at risk - Aggressive disease - Can claim compensation
How would immunohistochemistry help distinguish between a bronchogenic (2) adenocarcinoma from an epithelioid mesothelioma?
Mesothelioma: Usually positive: - Calretinin (i.e. mesothelial) - WT1 - EMA - CK 5/6 Usually negative (which are positive in adenocarcinoma) - CEA - TTF-1 - CK 7 Adenocarcinoma Positive: - CEA - TTF-1 Electron microscopy: - Mesothelioma: long microvilli - Adenocarcinomas: short
Toxicity
Problems RT: - Volume: Treating the entire pleura - IMRT: Dose of RT delivered to the contralateral lung, which increases the risk of pneumonitis Toxicity: - No G3 with IMRT Acute: - Dermatitis - Esophagitis - Fatigue/N/V - Pericarditis - Dyspnea - Arrhythmia? - Pneumonitis (20% G3-5) Late: - Pneumonitis - Esophagitis - Hepatitis
Discuss the use of radiation therapy in preventing or treating needle tract recurrence after thoracoscopy/thoracotomy
Prophylaxis to Port sites: Controversial - Rationale: Short course RT to needle track sites ↓ seeding - More recent data has questioned the utility of prophylactic RT - b/c recurrence is morbid and this is easy to do, it is still generally done Conficting results: A) O'Rourke (2007): - RCT - Prophylactic RT to drain sites did not statistically reduce the rate of seeding B) Bouting (1995) - RCT, 40 pts - Invasive dx procedures (cytology, needle biopsy, thoracoscopy, or chest tube placement) - Randomly assigned to (1) RT 21 Gy x3 vs (2) No treatment Results: - No chest wall recurrences in the RT patients - 40% recurrence without RT (p<0.001)
Extent of pleural lining in hemithorax
Runs close to the lung, except lower border (extends 3-5 cms below) Borders: Inferior: - MCL: 8th rib - MAL: 10th rib - Scapular: 12th rib Cervical pleura: - 2 inches above 1st costal cartilage
A previously well 45 year old woman presents with chest pain and is found to have an anterior mediastinal mass. A CT guided biopsy confirms thymoma, Type B1. She is discussed at a multidisciplinary meeting and undergoes resection. In general, what are the indications for adjuvant radiation therapy in the management (3) of thymoma?
a) Postoperative RT: - Incompletely resected thymomas - After resection for borderline tumours treated with neoadjuvant chemo - Consider for completely resected stage III (controversial Stage II) - Reduce local recurrence risk, but no survival benefit b) Definitive RT - Unresectable tumours (After neoadjuvant CT) c) Palliative