PLEURAL MESOTHELIOMA

DR TINKU JOSEPH

DM ResidentDepartment of Pulmonary Medicine

AIMS, KochiEmail-: tinkujoseph2010@gmail.com

Contents

Introduction Etiology/Risk factors Types Clinical presentation Diagnosis Staging Treatment

Mesothelioma is a form of Cancer that most frequently arises from the cells lining the sacs of the chest (the pleura) or the abdomen (the peritoneum) and almost always caused by exposure to asbestos.

The type of mesothelioma are pleural, peritoneal, and pericardial mesothelioma.

Mesothelioma-Introduction

At that time, the diagnosis was extremely controversial

(required autopsy examination) Today, the diagnosis is still problematic

– 15 % of cases cannot be differentiated from Adenocarcinoma

The term was first used in 1921 byEastwood & Martin

to describe primary tumors of the pleura

Mesothelioma: 1960

• Wagner, South African miners [Br J Ind Med]– first evidence implicating asbestos in the pathogenesis– landmark paper, began widespread investigation

• Incidence has reached “Epidemic”– European Experience: (2,700 - 9,000 deaths/yr.)

– U.S. Experience: Peaked in the 1970’s & since 1980

the incidence has been decreasing

Incidence

the increase in general incidence has been attributed

to the widespread use of asbestos in the

post-World War II period

[McDonald 1987]

Precautions were first taken in the U.S.Europe was “slow” to respondEffect on third-world countries

Incidence

• Industrialized Countries– 2 per million in females– 10 - 30 per million in males

Regional differences are due to the level of industrial activity

Areas with shipyards are at the highest risk

Type is also a Factor: Crocidolite & Amosite > Chrysotile

Incidence

The occurrence of mesothelioma is related to an

Occupational Exposure to Asbestos

Non-occupational environmental exposure leading

to it’s development is uncommon

Only 7.2 % of asbestos workers, will develop the disease Up to 50 % of patients, do not have any history of exposure

Incidence

cases due to exposure in buildings

with asbestos insulation

are extremely rare !

[Hughes et al. 1986: “quantitative risk”]

[Lilienfield 1991: “four cases in school teachers”]

Risk Factors

Asbestos

1.3 million workers exposed in the U.S.

construction industry

renovation, demolition heaviest exposures

General industry manufacture of asbestos products automotive brake and clutch repair housekeeping, custodial

Uses of AsbestosAsbestos has been used for centuries

Egyptians; Greeks & Romanswrapping Mummys; lamp wicks, cloth

Middle Agesinsulating armor

Industrial Revolutioninsulating boilers, steam pipes, turbines

Twentieth century – World War II + next 30 years. Insulating; fireproofing; sound-proofing; decorating; strengthening

Uses of Asbestos

Thermal system insulation

Surfacing materials Reinforcement of

materials Fireproofing Acoustic and decorative

plaster Textiles

Asbestos insulated pipe in utility space

Asbestos “CAB” siding

Uses of Asbestos

Friction materials (brakes, clutches, etc.)

Asphalt and vinyl felts

Papers and adhesives

Flooring and roofing materials

Filters, sealants and gaskets

Vinyl flooring

Sprayed-on fireproofing material

Types of Asbestos

Chrysotile

“White Asbestos”

Amosite “Brown Asbestos”

Crocidiolite (Dangerous)

Chrysotile fibers, high magnification

Most common:

Others Types:mostly found as

contaminants in other materials

Tremolite (possible contaminant in vermiculite)

Actinolite

Anthophyllite

Asbestos is an Inhalation Hazard

Breathable fibers are deposited in the alveoli.

Body’s defense mechanisms cannot break down the fibers.

Fibers may also travel to the pleura.

Lung Cancer/Asbestosis/ Mesothelioma.

Airborne asbestos fibers inhaled deep into the lung can cause damage.

Alveoli

Pleura

Carbon nanotubes are allotropes of carbon with awide array of applications in electronics, optics

similar dimensions and chemical property as asbestos

Carbon Nanotubes

What are the current applications of carbon nanotubes?

Wind turbines

Marine paints

Ice hockey sticks

Surf boards

Baseball bats

Maritime vessels

Handlebars

Seat posts

Scaffolding for bone growth

Golf clubs

Simian Virus 40

SV-40 is a polio vaccine contaminant in the 50s & 60s

BAP1 gene defects

BAP1 gene is located on chromosome 3BRCA1 Associated Protein-1regulate key histones and transcription factors related to tumor development

Radiation therapy

Radiation to supradiaphragmatic fields

Intrapleural thorium dioxide

Zeolites

OtherPotential

Causes

An example is erionite which is common in Turkey

3 Main Groups

Benign Localized Mesothelioma

“pleural fibroma” Unassociated with asbestos

exposure Paraneoplastic syndromes occur in

1/3 Arise from the visceral pleura Unless incomplete, surgical

resection is curative

Paraneoplastic Syndromes

Seen mostly in the Benign Localized Form Migrating Thrombitis Thrombocytosis Hemolytic Anemia Hypoglycemia Hypercalcemia Pulmonary Hypertrophic Osteoarthropathy

[Boutin 1998]

3 Main Groups

• Malignant Localized Mesothelioma– 20 % of all primary malignant pleural tumors are localized

– Present as Symptomatic Masses– Difficult to differentiate from Chest Wall Neoplasms

– Treatment Wide enbloc excision of all involved tissue Lung, Chest Wall, Soft Tissues, & Skin With incomplete excision, the prognosis is bad External beam radiation is of little benefit

3 Main Groups

Malignant Diffuse Mesothelioma Classical form Related to exposure Latent Period of 20 years Smoking is an associated factor

• not for mesothelioma, but for overall survival rate

TYPICAL SCENARIOmiddle-aged man with pleuritic chest pain, shortness of breath,

& a clear history of asbestos exposure

Malignant Mesothelioma

• 3 Cell Types

– Epithelial Type : 50 % of cases• most often confused with adenocarcinoma

– Mesenchymal Type : 16 % of cases

– Mixed Type : 34 % of cases

Pathogenecity

Benign pleural plaques are the most common manifestation of asbestos exposure

usually develop on the parietal or diaphragmatic pleura

malignant mesothelioma is thought to originate from the parietal pleura

high concentrations of asbestos fibers in the lung are associated with bronchial carcinoma

[Antilla 1993]

Clinical Presentation

Mean Age of Patients: 60– has been reported in children (unrelated to asbestos)

[Fraire 1988]

Clinical signs/symptoms depend on the stage:– TNM Classification

– Early-Stage Disease: Symptoms are Rare, Cough

– Late-Stage Disease: Pain, Dyspnea, Moderate Effusion

Mesothelioma is typically a unilateral disease – B/L in 10% of patients

Clinical Presentation

The initial chest radiograph leading to a

diagnosis of mesothelioma

reveals a pleural effusion 92 % of the time

7 % of the time, a Multinodular Pleural Tumor was found 0.5 % of the time, an Empyema 0.5 % of the time, a Spontaneous Pneumothorax

[Boutin 1993]

DIAGNOSIS

CXR Thoracentesis Chest C.T., MRI PET Thoracoscopy with Biopsy VATS

Chest X-Ray

Large unilateral pleural effusion- often with contralateral mediastinal shift.

Right side involved (60%) Pleural plaques/calcifications. Ipsilateral mediastinal shift (pleural

thickening) Advanced mesothelioma- mediastinal

widening (direct tumour invasion/lymph node/pericardial effusion), rib destruction, soft tissue masses extending into the chest wall

Thoracocentesis

Pleural fluid is an Exudate with little evidence of inflammation & a high number of mesothelial cells.

Elevated PF.Protein (4-5 g/dl) PF. LDH (>600 IU/L) Lymphocytic Low PH & glucose (advanced disease and poor prognosis) Highly viscous PF-: Elevated Hyaluronic acid level Cytology of the fluid is 30 % sensitive !

[Renshaw 1997]

Cytokine profile – Elevated IL-6, TGF-Beta, low levels of IL-1beta and TNF -alpha

Serum Markers

Soluble form of protein Mesothelin (SMRP) Found on normal mesothelial cells, mesothelioma

and ovarian cancer cells. Adjunctive role in diagnosis & screening (high

risk group)

IHC Markers

Malignant Mesothelioma Calretinin CK 5/6 Wilm’s tumour 1 (WT-1) D2 40

To differentiate Malignant Mesothelioma from Adenocarcinoma.

Adenocarcinoma (CEA, TTF-1, Leu M1, MOC 31, Ber-EP4, B72.3)

CT Scan

Chest C.T.• Irregular, nodular pleural

thickening• Spread into the diaphragm,

pericardium, chest wall, or mediastinal lymph nodes is difficult to assess

[Masilta 1991]

MRI Scan

Helpful in assessing the extend of disease – especially through the diaphragm into the peritoneal cavity.

Mediastinal nodes ( diagnostic accuracy = CT)

Better than CT (diaphragm, endothoracic fascia or chest wall

PET

Role is multifold Diagnosis/Staging Mediatinal lymph nodes, tumour

invasion into lung, thoracic wall, extra thoracic metastasis.

Treatment response to chemotherapy and radiotherapy

Role in planning radiation treatment. Screening of high risk patients

(potential future use)

Thoracoscopy

Thoracoscopy is indicated in any patient without a precise histopathological diagnosis in whom clinical & laboratory findings raise the suspicion of mesothelioma

V.A.T.S.

Mesothelioma takes on a “grape-like” appearance– patches of closely-spaced, smooth, translucid,

poorly-vascularized nodules with a clear to yellowish color

• not unique to mesothelioma

• also seen with metastatic cancer of the pleura

unlike benign inflammation (pleurisy),

the pleura becomes hard & non-elastic - with biopsy,

the cut edges do not bleed

V.A.T.S.

10 - 15 % of cases, the observed lesions are nonspecific

path report: “benign pleural inflammation”

The more unimpressive the picture, the more biopsies should be taken (up to 20)

Look for involvement of the Lung or Visceral Pleura

V.A.T.S.

98 % sensitive in establishing the diagnosis

Mortality is 1:8000

Complications are minimal– Subcutaneous Emphysema

– Localized Infection

– Minor Bleeding (< 100 cc)

[Viallat 1991]

Seeding of the Trocar Pathunknown incidence but can occurhas been documented after thoracentesis & blind pleural biopsy

can be prevented by performing Prophylactic

Radiotherapy after healing to the point of entry

Staging

Staging

Expected Survival

– Stage I: 16 months

– Stage II: 9 months

– Stage III: 5 months[Cohen 1995]

Median survival-: 9 to 12 months.

Depends on stage, histological subtype and concomitant medical problems.

Mortality

Mortality occurs due to-: local extension, respiratory failure.

Tumour extension below the diaphragm -: small bowel obstruction.

Arrythmias, heart failure, stroke

Prognostic factors

Poor prognostic factors-: Thrombocytosis, leukocytosis, low Hb, PUO, sarcomatoid or mixed histology, age >65, Male gender, poor performance status, associated smoking.

Good prognosis-: Epithelial histology (stage 1), age <65, performance status of 0 to 1, absence of chest pain.

CALGB Prognostic Index

EORTC Prognostic Index

Treatment

There is no single treatment which has

proven effective...

Surgery Radiation Chemotherapy Immunotherapy Gene Therapy

Treatment: Surgery

To ensure that surgery will be as curative as possible, resection must include:

– the Pleura: Stage Ia– the Lung: Stages Ib, II, and III

Many cases will require resection of the diaphragm,

pericardium, & chest wall

Treatment: Surgery

But does surgery improve survival ?

• Worn 1974, 248 Patients

– 62 Patients with Radical Pneumonectomy • 2-yr. Survival, 37 % 5-yr. Survival, 10 %

– Conservative Treatment• 2-yr. Survival, 12.5 % 5-yr. Survival, 0

%

Treatment: Surgery

• Probst 1990, 111 cases

– Median survival was longer after pneumonectomy than any other method (1.4 months)

operative mortality

for radical pneumonectomy, across the board,

is 25 %

Treatment: Surgery

A current review of all surgical series suggests that

treatment protocols including surgery

do extend survival...

– Pleurectomy(2-yr. Survival): 11- 35 %– Radical Pneumonectomy: 10 - 37 %

[Boutin 2008]

Treatment: Radiation

Despite in-vivo success against mesothelial cells,

this mode has not been proven successful in

the clinical setting

– Problem: size of the target area

– Post-radiation fibrosis can further aggravate pain • via compression of the chest wall & intercostal nerves

– Is effective to prevent “seeding”

Treatment: Chemotherapy

Responses seen in

20 -30 % of patients, but

without improvement in overall mortality

Doxorubicin Cisplatin Methotrexate Combined Protocols : 33 - 66 % response

New Approaches

Emerging Mesothelioma Treatments

Anti-Angiogenesis Treatment

Angiogenesis refers to the growth/development of blood vessels

Cancerous tumors require their own blood vessels to grow.

One possible method of treatment involves anti-angiogenesis drugs that inhibit tumor growth by preventing vascular endothelial growth factor, a protein secreted by some cancerous cells, from reaching receptors that help build blood vessels

Immunotherapy/Biological Therapy

Immunotherapy is using the body’s own immune system to target cancerous cells.

Researchers have discovered that the immune system can be capable of recognizing healthy cells vs. cancerous cells and can target cancerous cells for removal.

Substances used to promote immunotherapy are called biological response modifiers (BRM)s

• BRMs may be used to: Enhance the immune system Eliminate, regulate, or suppress body responses that

permit cancer growth. Make cancer cells more susceptible to destruction by

the immune system. Alter cancerous cell growth patterns to those of normal

cells. Block or reverse the transformation of a normal cell

into a cancer cell. Prevent a cancer cell from spreading (metastasis)

Immunotherapy

Intrapleural delivery of cytokines are currently being tested

– Interferon-Gamma

– Interleukin-2

Studies began in 1987 (150 patients)

– Response Rates: 6 - 44 %

– Effect on Survival is unknown at present[Dreisen 1992]

Treatment: Gene Therapy

Trials have begun to evaluate the genetic

transfer

of thymidine kinase

(from herpes virus to adenovirus)

too early to judge effect or outcome…

[Smythe 2010]

Photodynamic Therapy PDT

Based on the premise that cells treated with photosensitive drugs will die when exposed to light at particular frequencies.

Drug is administered intravenously and accumulates in diseased cells and is removed from healthy cells.

Laser light is administered to cancerous sites and the light activates an active form of oxygen that destroys surrounding cancer cells

Timing is crucial because the therapy needs to occur when the drug has been removed from healthy cells but is still present in cancerous cells

Virotherapy

Virotherapy attempts to attack a tumor by using a virus that is created to attack certain cells

This form of treatment is in the laboratory stages but virotherapy has produced some promising results

Management of Dyspnoea

Repeated pleural aspiration Repeated pleural aspiration Pleurodesis –Pleurodesis –

(Talc/Betadine/Tetracycline)(Talc/Betadine/Tetracycline)

Management of pain

Due to the complex nature of pain in mesothelioma, adjunct analgesia may frequently be required in addition to opiates. In cases of refractory pain unresponsive to the usual measures, a specialist pain management or specialist palliative medicine opinion should be sought.

Occasionally neuroablative techniques may be required.

Palliative radiotherapy may be proposed and effective in treating pain due to tumour nodules

Conclusions

Mesothelioma kills - slowly & effectively…

Early-stage disease: most important predictor of outcome

To find “early-stage disease”, remember the risk factors– Age between 55 - 65– Previous occupational exposure to asbestos– Pleural Effusion– C.T. / MRI (with nodular lesions of the parietal

pleura)

Conclusions

• Diagnosis is best established by V.A.T.S. Following invasive procedures, “seeding”

will occur & should be treated by radiotherapy

• Treatment: “it is currently, the clinician’s choice” Multimodal approach including radical

surgery “Limited-Role for Limited-Surgery”

• Palliative

• Relief of symptoms