1. Disorders of the Pleura, Mediastinum, Diaphragm, Chest Wall and Lung Cancer
Maximino G. Bello III, MD, FPCP, FPSMO
Executive Secretary, Cancer Institute

2. Take note! All exams are Harrison based
Rapid advances in oncology, new findings may supersede Harrison
Take note if I stressed a particular fact or statement
Topics not discussed in today's lecture does NOT mean it would not be included in exams

3. Pleural diseases Pleural effusion Pneumothorax
Pleural space from the capillaries in the parietal pleura removed via lymphatics
Interstitial spaces from the lung via visceral pleura
Peritoneal cavity via diaphragm
Pneumothorax
Air in the pleural space

5. Diagnostic approach Transudate: systemic factors
Exudate: local factors
Light’s Criteria
Pleural fluid CHON /serum CHON >0.5
Pleural fluid LDH/serum LDH >0.6
Pleural fluid LDH more than 2/3 normal upper limit for serum

6. Light’s Criteria misidentifies ≈25% of transudates as exudates

7. Light’s Criteria Transudate CHF Cirrhosis PE Nephrotic syndrome
Peritoneal dialysis
SVC
Myxedema
Exudate
Infectious
Neoplastic
GI disease
Collagen vascular dse
P CABG
etc

10. Parapneumonic effusions
Associated with bacterial infection, lung abscess or bronchiectasis
Empyema: grossly purulent effusion
Condensed milk
“significant effusion”
Lateral decubitus view shows 10mm layering of fluid drainage of effusion

11. Drainage of effusion
Need for a more invasive procedure (other than thoracentesis)
Loculated pleural effusion
Pleural fluid pH <7.20
Pleural fluid glucose < 3.3mmol/L
+ gram stain or culture of the pleural fluid
empyema

12. Effusion secondary to malignancy
Lung and breast carcinoma and lymphoma
75% of malignant effusion
Dyspnea is NOT proportionate to the amount of effusion
Lung metastasis
Treatment
Drainage of the fluid sclerosing agent treatment of the malignancy

13. Effusion secondary to mesothelioma
Primary tumor of the mesothelial cells
Line the pleural cavity
Significant asbestos exposure
Imaging:
Effusion, thick pleura, collapse hemithorax
Treatment:
Surgery
pretexemed

16. Pneumothorax Primary spontaneous pneumothorax Treatment: aspiration
Rupture of apical bleb
It typically occurs in tall, thin boys and men between the ages of 10 and 30 years
rarely occurs in persons over the age of 40.
Appears almost exclusively in smokers
½ will have recurrences
Treatment: aspiration

17. Pneumothorax Secondary spontaneous pneumothorax Treatment COPD
More fatal lesser physiologic reserve
Treatment
Tube thoracostomy

19. Pneumothorax Traumatic pneumothorax Tension pneumothorax Penetrating
Non penetrating injuries
Tension pneumothorax
Medical emergency
During resuscitation
Cyanosis, hypotension

21. Most Diaphragmatic Hernia’s are detected in childhood.
Rare in adults!

22. Diaphragmatic Hernia Congenital diaphragmatic hernia Bochdalek:
More common
postero-lateral diaphragmatic hernia
majority of Bochdalek hernias (80-85%) occur on the left side
Morgagni
Less common
Anterior, right

24. Mediastinum Occupies the central portion of the thoracic cavity
Boundaries:
Lateral- pleural cavity
Superior- thoracic inlet
Inferior- diaphragm
Anterior- sternum
Posterior- chest wall
anterior
posterior
middle
De Vita, et al .Principles & Practice of Oncology 8th ed 24

25. Mediastinal tumors: Feature Thymoma Lymphoma Germ cell tumor
Mesenchymal
Incidence
- most common
anterior Mediastinal
neoplasm
% of
Mediastinal tumors
- equal in male and
female
- ages
% of
primary Mediastinal
masses
- 2nd most common
mass
- Most Mediastinal
lymphomas are
seen in the
anterosuperior
mediastinum.
-15% of anterior
Mediastinal tumors in
adults.
(24% in children)
- Rarely, they are
found in the posterior
mediastinum
- 6% of Mediastinal
tumors.
- More than 50%
are malignant

26. Mediastinal tumors: Feature Thymoma Lymphoma Germ cell tumor X-ray
Mesenchymal
Radiographic findings:
X-ray
smooth mass in the upper half of the chest.
Overlying the superior portion of the cardiac shadow.
-The mass projects predominantly into one of the hemithoraces.
Lobulated with enlargement of hilar and media- stinal lymph nodes.
- well defined mass occasionally containing calcifications.
- Mediastinal widening on CXR

27. Mediastinal tumors: Feature Thymoma Lymphoma Germ cell tumor
Mesenchymal
Radiographic findings:
CT scan
- demonstrates uniform enhancement
conglomerate of lymph nodes
discrete enlarged LN with cystic degeneration
lobulated, asymmetrical, homogenous tumors
with/ without cystic components
can determine components of tumor (fat, soft tissue)
defines the relation of tumor to adjacent tissues.

28. Mediastinal tumors: Feature Thymoma Lymphoma Germ cell tumor
Mesenchymal
Signs and symptoms
- 50% asymptomatic
- symptoms due to myasthenia in 35% of patients
- others with substernal pains, dyspnea, cough
- Invasive thymoma cause local compression /svc syndrome
-Majority of are symptomatic at diagnosis.
- Common: fever, weight loss, night sweats
- Compression symptoms: pain, dyspnea, stridor, or superior vena cava syndrome
- Associated pleural effusions are common
malignant tumors are symptomatic in 85% of patients:
chest pain,
hemoptysis,
cough,
fever,
weight loss.
- Superior vena caval syndrome is occasionally seen
- Compressive sign and symptoms based on adjacent tissues involved.

29. Made Ridiculously simple!
Lung Cancer
Made Ridiculously simple!

30. MORTALITY: TEN LEADING (10) LEADING CAUSES Number and rate/100,000 Population Philippines 5-Year Average ( ) & 2005

32. US Mortality, 2005 No. of deaths % of all deaths Rank Cause of Death
1. Heart Diseases 652,
2. Cancer ,
3. Cerebrovascular diseases 143,
4. Chronic lower respiratory diseases 130,
5. Accidents (unintentional injuries) 117,
6. Diabetes mellitus 75,
7. Alzheimer disease ,
8. Influenza & pneumonia 63,
Nephritis* ,
10. Septicemia ,
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2005, there were 559,312 cancer deaths in the US.
*Includes nephrotic syndrome and nephrosis.
Source: US Mortality Data 2005, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

33. 2008 Estimated US Cancer Deaths*
Men 294,120
Women 271,530
Lung & bronchus 31%
Prostate 10%
Colon & rectum 8%
Pancreas 6%
Liver & intrahepatic 4% bile duct
Leukemia 4%
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin % lymphoma
Kidney & renal pelvis 3%
All other sites %
26% Lung & bronchus
15% Breast
9% Colon & rectum
6% Pancreas
6% Ovary
3% Non-Hodgkin lymphoma
3% Leukemia
3% Uterine corpus
2% Liver & intrahepatic bile duct
2% Brain/ONS
25% All other sites
Lung cancer is, by far, the most common fatal cancer in men (31%), followed by prostate (10%), and colon & rectum (8%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death.
ONS=Other nervous system.
Source: American Cancer Society, 2008.

34. HOSPITAL TUMOR REGISTRY REPORT 2000-2007
TOP TEN CANCER SITES (both sexes)
SITE MALE FEMALE TOTAL 1. BREAST Lungs Colon/rectum cervix uterii Nasopharynx Uterus/ endometrium 7. prostate thyroid gland blood/ bone marrow 10. lymphomas total

35. Change in the US Death Rates* by Cause, 1950 & 2005
Rate Per 100,000
1950
2005 ?
Compared to the rate in 1950, the cancer death rate decreased slightly in 2005, while rates for other major chronic diseases decreased substantially during this period.
Heart Diseases
Cerebrovascular Diseases
Influenza & Pneumonia
Cancer
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2005 Mortality Data: US Mortality Data 2005, NCHS, Centers for Disease Control and Prevention, 2008.

36. Lung Cancer
: 13%
: 13%
: 16%

37. Worldwide Incidence and Mortality for Lung Cancer
Lung cancer is the most common cancer in the world
Smoking is the most important risk factor
World Incidence1
World Mortality1
Lung Cancer
1.5 Mio
90%
Worldwide Incidence and Mortality for Lung Cancer
Lung cancer is the most common cancer in the world, with 1.3 million new cases diagnosed every year, and it is the leading cause of cancer-related mortality
Asia accounts for 49% of the worldwide incidence and mortality of cancer, Europe accounts for 28% of the incidence and 29% of the mortality, and North America accounts for 17% of the incidence and 15% of the mortality
Central and South America account for 4% of the worldwide incidence and mortality, while Africa and Oceania* each account for 1% of the incidence, with Africa accounting for 2% and Oceania accounting for 1% of worldwide cancer mortality
* Includes Australia and New Zealand.
Lung Cancer: Kamangar et al. J Clin Oncol. 2006;24:

38. Inherited cancer syndrome
Host Susecptibility
Family Hx
Inherited cancer syndrome
P53 mutation
EGFR mutation
Retinoblastoma
SNP variation at 15q24–15q25.1
susceptibility and risk also increase with reduced DNA repair capacity ERCC1
Molecular Evolution of Lung Cancer.
Environmental factors, such as tobacco smoke, and genetic susceptibility interact to influence carcinogenesis. Factors that are unrelated
to smoking — including genetic, hormonal, and viral (e.g., human papillomavirus) factors — have been suggested.2 Tissue injury (e.g.,
from tobacco smoke, reflected in the discolored smoking-related lungs) initially occurs in the form of genetic and epigenetic changes (e.g.,
mutations, loss of heterozygosity, and promoter methylation) and global transcriptome changes (e.g., inflammation and apoptosis pathways).
These changes can persist long term3,4 and eventually lead to aberrant pathway activation and cellular function (e.g., dysregulated
proliferation and apoptosis) to produce premalignant changes, including dysplasia and clonal patches. Additional changes can result in
angiogenesis, invasion and early-stage cancer, and advanced cancer and metastasis.5 Many molecular changes in earliest-stage cancer
also occur in advanced disease.6,7 Premalignant patches contain clones and subclones (inset), which can involve loss of heterozygosity,
microsatellite instability, and mutations (e.g., in p53 and epidermal growth factor receptor [EGFR]). Lung cancers unrelated and related to
smoking have strikingly different molecular profiles, including those of mutations in p53, KRAS, EGFR, and HER2. Smoking-related patches
and primary cancers (usually squamous-cell carcinoma and small-cell lung cancer) most often develop in the central airway.4,8 Most tumors
that are not related to smoking are adenocarcinomas and develop in the peripheral airways. Molecular markers can signify risk (in people without
cancer), prognosis (outcome independent of treatment), and sensitivity to treatment through predictive markers. Such stage-specific markers
can span the course of disease from its early stages through its late stages. They also can help define mechanisms of resistance to therapy.

39. Clonal Evolution
Changes in certain genes occur in nonmalignant lung tissue of smokers and patients with lung cancer
Early events in the development of NSCLCA include loss of heterozygosity at chromosomal region 3p21.3 , 3p14.2, 9p21 (p16), and 17p13 (p53)
Molecular Evolution of Lung Cancer.
Environmental factors, such as tobacco smoke, and genetic susceptibility interact to influence carcinogenesis. Factors that are unrelated
to smoking — including genetic, hormonal, and viral (e.g., human papillomavirus) factors — have been suggested.2 Tissue injury (e.g.,
from tobacco smoke, reflected in the discolored smoking-related lungs) initially occurs in the form of genetic and epigenetic changes (e.g.,
mutations, loss of heterozygosity, and promoter methylation) and global transcriptome changes (e.g., inflammation and apoptosis pathways).
These changes can persist long term3,4 and eventually lead to aberrant pathway activation and cellular function (e.g., dysregulated
proliferation and apoptosis) to produce premalignant changes, including dysplasia and clonal patches. Additional changes can result in
angiogenesis, invasion and early-stage cancer, and advanced cancer and metastasis.5 Many molecular changes in earliest-stage cancer
also occur in advanced disease.6,7 Premalignant patches contain clones and subclones (inset), which can involve loss of heterozygosity,
microsatellite instability, and mutations (e.g., in p53 and epidermal growth factor receptor [EGFR]). Lung cancers unrelated and related to
smoking have strikingly different molecular profiles, including those of mutations in p53, KRAS, EGFR, and HER2. Smoking-related patches
and primary cancers (usually squamous-cell carcinoma and small-cell lung cancer) most often develop in the central airway.4,8 Most tumors
that are not related to smoking are adenocarcinomas and develop in the peripheral airways. Molecular markers can signify risk (in people without
cancer), prognosis (outcome independent of treatment), and sensitivity to treatment through predictive markers. Such stage-specific markers
can span the course of disease from its early stages through its late stages. They also can help define mechanisms of resistance to therapy.

40. Lung Cancer: Histology The Clinical Importance
Histological types
NSCLC 80%
Non Small Cell Lung Cancer
SCLC 20 %
Small Cell Lung Cancer
10 %
Large Cell Ca.
50 %
Adeno-ca.
40 %
Squamous-ca.
NSCLC Histological Subtype
non-squamous: 60%
squamous: 40%
Grouping bet. Squamous vs non squamous is an oncologic/clinical classification
Clinical Classification are always clinically useful

41. Lung Cancer NSCLCA AJCC staging (I to IV) Less chemo sensitive
Less radio sensitive
Established role of surgery
Small Cell Lung Cancer
Veterans Affairs Staging (limited vs. extensive)
More chemo sensitive
More radio sensitive
No role for surgery

43. The difference Squamous Harder to treat Not susceptible to TKI
Stronger smoking association
Males
TX: gemcitabine
Non squamous
More “easier to treat”
Sensitive to TKI
Lesser smoking association: adenocarcinoma
Females: adenocarcinoma
TX:
TKI’s bevasizumab & pretexemed

45. Staging

46. Surgery + adjuvant chemo platinum + vinorelbine platinum + gemcitabine
NSCLC treatment
Stage IIIB/IV
Stage I
Stage II
Stage IIIA
The majority
Chemotherapy
Surgery +
chemotherapy
Or chemoRT
Surgery + adjuvant chemo
Surgery
Chemoradio
therapy
Chemotherapy
1st line
2nd line
pemetrexed
platinum + docetaxel
platinum + vinorelbine
docetaxel
3rd line
erlotinib
platinum + paclitaxel
platinum + gemcitabine
gefitinib (Asia)
Platinum = Cisplatin or Carboplatin

48. NSCLC Tumor Stages: IIIB and IV
Stage IIIB
Stage IV
ERBITUX

49. Clinical Manifestations
Tumors in the large airways
- cough, wheezing, hemoptysis
With atelectasis and with pleural space involvement
- pleuritic chest pain
Tumors invading the chest wall
- stabbing or burning radicular pain

50. Methods to Establish Tissue Diagnosis
Sputum Cytology
-sensitivity is 65% (22%- 98%)
-molecular techniques (p53, A2/B1
expression,k-ras)
Percutaneous Fine-Needle Aspiration
-fluoroscopic or CT-guided techniques
-The positive yield exceeds 95% (even if
lesions are less than 1 cm in diameter)

51. Methods to Establish Tissue Diagnosis
Bronchoscopy
minimal morbidity,safe
visualization of the tracheobronchial tree to the 2nd or 3rd segmental divisions
cytologic or histologic specimens can be obtained
-diagnostic yield of FOB with cytologic
brushings or biopsy of visible lesions
exceeds 90%

52. Methods to Establish Tissue Diagnosis
Mediastinoscopy, Mediastinotomy, and Endoscopic Ultrasound-Fine-Needle Aspiration
most accurate technique to assess paratracheal, proximal peribronchial, and subcarinal lymph nodes in lung cancer patients
indicated in any patient suspected of having locally advanced disease
mediastinoscopy before surgical intervention for lung cancer has evolved during recent years

53. Methods to Establish Tissue Diagnosis
Thoracentesis
identify inoperable, pleural disease (T4)
unless malignant cells are identified, a bloody pleural effusion should be considered traumatic
diagnosis of cancer in can be established in 70% of malignant effusions by thoracentesis
Thoracoscopy
Video-assisted thoracoscopy is frequently used for the diagnosis, staging, and resection of lung cancer
valuable for evaluation and palliation of suspected pleural disease, particularly when thoracentesis has been nondiagnostic

54. Methods to Establish Tissue Diagnosis
Thoracotomy
diagnosis often can be obtained via multiple FNAs with immediate cytologic analysis, or incisional (or preferably excisional) biopsy with frozen section
intraoperative biopsies of hilar and mediastinal lymph nodes
resection of the primary lesion and complete mediastinal lymph node dissection

55. Comparison of First-Line Doublet Trials: Treatments
ECOG 1594 (n = 1,207)
Paclitaxel 135 mg/m2 over 24 hrs day 1
Cisplatin 75 mg/m2 day 2 q 3 wks
Paclitaxel 225 mg/m2 over 3 hrs day 1
Carboplatin AUC 6 day 1q 3 wks
Gemcitabine 1,000 mg/m2 days 1, 8, 15
Cisplatin 100 mg/m2 day 1 q 4 wks
Taxotere 75 mg/m2 over 1 hr day 1
Cisplatin 75 mg/m2 day 1q 3 wks
SWOG 9509 (n = 408)
Vinorelbine 25 mg/m2 /wk
Cisplatin 100 mg/m2 day 1q 4 wks
Paclitaxel 225 mg/m2 over 3 hrs day 1
Carboplatin AUC 6 day 1q 3 wks

56. Comparison of First-Line Doublet Trials: Treatments
TAX 326 (n = 1,218)
Vinorelbine mg/m2 days 1, 8, 15, 22
Cisplatin 100 mg/m2 day 1q 4 wks
Taxotere 75 mg/m2 over 1 hr day 1
Cisplatin 75 mg/m2 day 1q 3 wks
Taxotere 75 mg/m2 over 1 hr day 1
Carboplatin AUC 6 day 1q 3 wks
ILCP (n = 612)
Vinorelbine 25 mg/m2 /wk 12 wks, then every other wk
Cisplatin 100 mg/m2 day 1q 4 wks
Paclitaxel 225 mg/m2 over 3 hrs day 1
Carboplatin AUC 6 day 1q 3 wks
Gemcitabine 1,250 mg/m2 days 1, 8
Cisplatin 75 mg/m2 day 2q 3 wks

57. Comparison of First-Line Doublet Trials: Median Survival Time
Median Survival (months)
Vin + Cis
Pac + Carbo
Pac + Cis
Gem + Cis
Tax + Cis
10.1
11.3
9.9
9.5
10.0
9.8
7.8
8.1
7.4
8.6
9.4
P = 0.044
Tax + Carbo

58. for patients across all histologies
Achievements in NSCLC
for patients across all histologies
Median OS
Months
1950‘s
1970‘s
1990‘s
1998 -
1995
2007
2008
3rd Generation
Chemotherapy
11,12
5, 10
9, 8
9, 3, 6, 7
2, 8, 4, 7
4, 5, 6, 7
3, 4 2 1
30 years: step by step increase in median OS ranged from 1-2 months
1. Pirker et al, JCO 2008; 18S Abstract 3; 2. Scagliotti et al. JTO 2007; 2, 8 (Suppl 4), 308 (Abstr. PRS-03); 3. Fosella et al. JCO 2003; 21: ; 4. Schiller et al., NEJM 2002; 346: 92–98; 5. Bonomi et al. JCO 2000; 18: ; 6. Kelly et al. JCO 2001; 19:3210–3218; 7. Scagliotti et al. JCO 2002; 21: ; 8. Alberola et al. JCO 2003; 9. Wozniak et al. JCO 1998; 16: ; 10. Cardenal et al. JCO 1999; 17: 12-18; 11. Roszkowiski et al. Lung Cancer 2000; 27: ; 12. Cullen et al. JCO 1999; 17:

59. xx/xx/xxxx
Longest overall survival achieved in non-squamous metastatic NSCLC patients with Avastin
Platinum-based doublet + Avastin 12.3 months
2000s
1990s
1980s
1970s
Platinum-based doublets 8–10 months
Single-agent platinum 6–8 months
Advances in the treatment of non-squamous metastatic NSCLC have led to increasingly longer overall survival (OS). In the 1970s, OS with best supportive care was 2–5 months. OS improved in the 1980s and 1990s with the introduction, respectively, of single-agent platinum (6–8 months) and platinum-based doublet chemotherapy (8–10 months) (Schiller et al. 2002).
Avastin in combination with platinum-based doublet chemotherapy has achieved the longest OS in patients with non-squamous metastatic NSCLC (12.3 months) (Sandler et al 2006).
References
Schiller JH, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–8.
Sandler A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50.
BSC
2–5 months
Median survival (months)
BSC = best supportive care
Schiller, et al. NEJM 2002
Sandler, et al. NEJM 2006
Editor: Presentation name here

60. General Conclution about NSCLCA Chemotherapy
“platinum based doublet”
Platinum: cisplatin or carboplatin
All are equally effective
None is superior over the other
Toxicity is different
Addition of a biologic agent improves OS
Cetuximab
bevasizumab

61. Thank you!
Questions??

62. Modes of Dissemination