DISEASE MESOTHELIOMA

Friday, September 25, 2009

Definition of Risk Assessment

at the margin of our understanding of
the health effects of chemicals and
other substances

best defined as the determination of
pathology caused by human
production and activity, with the
understanding that "pathology" is a
change in some aspect of human
anatomical structure or function

Definition of Risk Assessment

Risk Assessment, or risk evaluation,
is a scientific/ mathematical discipline
which is

a substantive, changing and
controversial field

Risk Analysis

This is the overall term for all of
Risk Science

It has four elements:

- Risk Assessment (Risk Evaluation)

- Risk Communication

- Risk Perception

- Risk Management (Risk Characterization (EPA))

Buzzword Alert!

There are a number of technical
terms in this lecture

Yes, you have to know them!

These terms have precise
meaning, even though you will
often see them MIS-used.

Since risk assessment is (or aims
to be) a scientific activity we must
agree on terminology

Risk Assessment

Definitions: Risk Analysis, Risk Assessment
(Evaluation) and their components

A detailed look at HAZARD EVALUATION

Risk Perception, Risk Communication, Risk
Management

An example of risk assessment: Mesothelioma
among Quebec asbestos mining area women.

Risk and the precautionary principle

Thursday, September 17, 2009

Malignant Mesothelioma - Conclusion

The increasing incidence worldwide of
malignant mesothelioma has created
an awareness of the need for new
ways to treat this disease.

In the meantime, we should continue
to provide extremes psychosocial
support as well as palliative care for
our patients with MM.

Malignant Mesothelioma - Treatment

Surgery:
most useful for palliation – for local
control of recurrent effusions. This can be either
radical resection (extrapleural pneumonectomy) or
debulking surgery vs VATS.

Chemotherapy:
poor response rates (15-20%) in
most cases. Pemetrexed and cisplatin, Gemcitabine
with cisplatin are common chemo-regimen used
currently.

Radiotherapy:
MM is resistant to traditional
radiotherapy. Local radiation to surgical sites
prevent seeding of tumor, and can provide
palliative relief of somatic chest-wall pain.

Immunotherapy:
studies in animal and clinical
trials have shown some tumor response to trials of
IFN-alpha, intrapleural IL-2, GM-CSF

Malignant Mesothelioma - Prognostic Factors

Median survival of patients with MM from time of
diagnosis is approx 12 months.

Worse prognosis in the following pts:

1. Male
2. Those with extensive diseases
3. Poor performance status
4. Elevated white-cell counts, Anemia,
Thrombocytosis
5. Sarcomatoid histologic findings
6. Expresssion of certain biochemical
markers(VEGF), evidence of SV40 virus in the
tumor

Histopathology

Since cytologic findings may be inconclusive at
times, tumor biopsy is often needed.

Cytokeratin staining helps to confirm invasion and
to distinguish MM from sarcoma or melanoma.

MM is characterized by the presence of staining for
EMA, calretinin, WT1, mesothelin, and the absence
of staining for antigens such as CEA, tumor
glycoproteins B72, MOC-31.

Electron microscopy also helps to distinguish MM
from adenocarcinoma or to differentiate
desmoplastic or sarcomatoid mesothelioma from
fibrous pleuritis.

Malignant Mesothelioma - Cytology

Cytologic evidence of MM in the pleural or ascitic
fluid is found in 33-84% of cases.

A group of immunohistochemical markers is
important in the diagnosis of MM.

Initially, one has to differentiate if the tissue is
mesothelial in origin by checking for the presence
of markers such as calretinin, WT 1 antigen.

Secondly, one has to determine if the cells are
malignant by testing for the marker known as
epithelial membrane antigen (EMA, aka CA 15-3
and mucin-1)

Cytologic analysis is sufficient to make a diagnosis
with a high level of confidence in about 80% of the
cases, if done by an experienced pathologist.

Malignant Mesothelioma - Diagnostic Imaging

CXR: shows pleural effusion, and
occasionally may show a pleural-based
mass.

CT chest: often show pleural effusion alone
(74%) or pleural-based masses (92%) +/-
thickening of the interlobular septa (86%).

MRI: is useful in determining the extent of
the disease. To see if there is invasion of
local structures such as ribs, diaphragm, etc

PET scan: helps to distinguish benign from
malignant pleural masses. It is also useful
for detecting extrathoracic disease,
especially, if there is lymph-node
involvement.

Malignant Mesothelioma - Clinical Features

Unexplained pleural effusions with
dyspnea, as well as chest wall pain

About 80% of patients with pleural
malignant mesothelioma are male.

Cancer Syndrome: wt loss, fever, night
sweats, cachexia, fatigue,
thrombocytosis, high ESR, low
albumin, and anemia. Are usually
manifested in the later stages.

Wednesday, September 16, 2009

Asbestosis:The Ancient Curse - Pathogenesis

There are 4 principal processes by which asbestos
affects the pleura

The fibers irritate the pleura, thereby inducing
scarring or a more malignant process

The fibers may pierce the mitotic spindle of cells,
thereby disrupting mitosis leading to
chromosomal damage

They also induce the generation of iron-related
reactive oxygen species (ROS) causing DNA
damage

Asbestos also induces phosphorylation of the
mitogen-activated protein (MAP) kinases which
increases the expression of early-response proto-
oncogenes

Tuesday, September 15, 2009

Asbestosis:The Ancient Curse

Epidemiology

Incidence of malignant mesothelioma is
rising worldwide due to exposure to
asbestos especially in developing countries

In the 1960s, the first evidence of a link
btw MM and both occupational as well as
incidental asbestos exposure was reported
in S. Africa

It may have reached its peak in the U.S
since people are now more aware of the
dangerous effects of asbestos.

Monday, September 14, 2009

Asbestos Exposures, Inhalation of Asbestos, Diagnosis, Management

Asbestos exposures peaked in the United
States in 1940-1980, but continue to occur
today

Inhalation of asbestos can lead to

- parenchymal asbestosis,
- pleural abnormalities,
- lung carcinoma, and
- mesothelioma

Diagnosis involves

- exposure and medical history,
- physical examination,
- chest radiography,
- pulmonary function tests, and
- other tests as needed

Management focuses on:

- Preventing further exposures
- Smoking cessation
- Monitoring to aid early detection
- Patient education

Communication with the Patient

Obtain patient’s employer contact
information to facilitate occupational
exposure prevention (OSHA mandates
PPE and medical surveillance)

Counsel patient regarding smoking
cessation

Have patient consult you for health changes

Provide and review patient education and
instruction sheet with patient

Lung Cancer and Mesothelioma - Disease Management

Treatment Strategy

- Early diagnosis

- Surgery

- Chemotherapy

- Radiation

Disease Management

Asbestos-associated
Disease

Parenchymal
Asbestosis and
Asbestos-Related
Pleural Abnormalities

Treatment Strategy

Stopping additional exposure

Careful monitoring to facilitate early diagnosis

Smoking cessation

Regular influenza and pneumococcal vaccines

Pulmonary rehabilitation as needed

Disability assessment

Aggressive treatment of respiratory infections

Other Tests

CT and HRCT

BAL and lung biopsy

ABGs and pulse oximetry

Colon cancer screening

Chest Radiograph Findings: Mesothelioma

Pleural effusions

Pleural mass

Diffuse pleural
thickening

Chest Radiograph Findings: Asbestos-Related Pleural Abnormalities

Pleural plaques

Areas of pleural thickening

Sometimes with calcification

Pleural effusions

Diffuse pleural thickening

Lobulated prominence of
pleura adjacent to thoracic margin
(over ¼ of chest wall)
Interlobar tissue thickening

Rounded atelectasis

Rounded pleural mass

Bands of lung tissue radiating outwards

Chest Radiograph Findings: Parenchymal Asbestosis

Small, irregular oval
opacities

Interstitial fibrosis

“Shaggy heart sign”

Pulmonary Function Tests

Disease

Parenchymal Asbestosis

Pulmonary Function Test Findings

Reduction in FVC; normal FEV1/FVC Ratio

Reduction in FEF (25%-75%)

Restrictive pattern with decreased DLCO

Or, mixed obstructive/restrictive pattern
(reduced FEV1/FVC associated with
reduced FVC)

Disease

Asbestos-Related Pleural Abnormalities

Pulmonary Function Test Findings

Often normal

Reduced FVC can be associated with
diffuse pleural thickening

Physical Examination

Focus on lungs, heart, digits, and
extremities

Pulmonary auscultation to detect
bibasilar inspiratory rales (not always present)

Observation of other signs, such as
clubbing of the fingers and cyanosis

Patient History

Exposure History :

Work history

Source, intensity, duration, and
frequency of exposure

Time elapsed since first exposure

Workplace dust measurements or description of
exposure scenario

Use of personal protective equipment

Paraoccupational exposures

Sources of environmental exposure

Medical History :

History of smoking

History of other conditions

Mesothelioma - Signs and Symptoms

Disease

Mesothelioma

Signs and Symptoms

Usually: None (until later stages)
Sometimes: Dyspnea, chest pain, and fatigue

Lung Cancer - Signs and Symptoms

Disease

Lung Cancer

Signs and Symptoms

Usually: None (until later stages)
Sometimes: Fatigue, weight loss, or chest pain

Clinical Presentation

Disease

Asbestos-Related

Pleural Abnormalities

Signs and Symptoms

Usually: None

Sometimes: Progressive dyspnea and intermittent
chest pain (depending on the type of pleural
abnormality)

Clinical Presentation

Disease

Parenchymal Asbestosis

Signs and Symptoms

Insidious onset of dyspnea on exertion
Fatigue

Diagnosis

Medical evaluation of all patients should
include:

- Assessment of clinical presentation

- Exposure history

- Medical history

- Physical examination

- Chest radiograph and pulmonary function
tests

Radiologic and laboratory testing can include:

- CT or HRCT

- BAL

- Lung biopsy (rarely needed)

Risk Factors

Nature and extent of exposure:

Concentration of asbestos fibers

Duration of exposure

Frequency of exposure

Cigarette smoking

Other Extrathoracic Cancers

Colon cancer

Possibly cancer of larynx, stomach,
kidney, esophagus

Association with asbestos exposure
remains controversial

Regular colon cancer screening for
people over age 50 years

Screening for other extrathoracic
cancers not recommended

Malignant Peritoneal Mesothelioma

“Doughy” feeling on abdominal
palpation

Male:female incidence is 1.5:1
(compared to 5:1 with pleural tumor)

Rapidly invasive and rapidly fatal

Often associated with high-dose
asbestos exposures

Rare

Malignant Pleural Mesothelioma

Tumor arises from the thin serosal
membrane surrounding the lungs

Rapidly invasive

Rare, although incidences are
increasing

Long latency period: Usually 30-40 years

Lung Carcinoma

Risk depends on:

Level, frequency, and duration of exposure

Time elapsed since exposure

Age at time of exposure

Smoking history (synergistic)

Individual susceptibility factors (under
investigation)

Latency period: 20-30 years

Asbestos-Related Pleural Abnormalities

Four types of abnormalities:

- Pleural plaques

- Benign asbestos pleural effusions

- Diffuse pleural thickening

- Rounded atelectasis

Mostly asymptomatic, though some
can cause dyspnea or cough

Latency periods: 10-30 years
(shorter latency is for pleural effusion)

Parenchymal Asbestosis

Diffuse interstitial fibrosis with:

- Restrictive pattern of disease on pulmonary
function testing (but can see mixed pattern)

- Impaired gas exchange

- Progressive exertional dyspnea

Radiographic changes: >10 years

Latency period: 20-40 years

Asbestos-Associated Diseases

Respiratory diseases:

Parenchymal asbestosis

- Asbestos-related pleural abnormalities

- Lung carcinoma

- Pleural mesothelioma

Nonrespiratory diseases:

- Peritoneal mesothelioma

- Possibly, other extrathoracic cancers

- Rarely, cor pulmonale or constrictive pericarditis

Pathogenesis

Asbestos fibers induce pathogenic
changes via:

- Direct interaction with cellular macromolecules

- Generation of reactive oxygen species (ROS)

- Other cell-mediated mechanisms

These changes can lead to cell injury,
fibrosis, and possibly cancer

Asbestos is genotoxic and carcinogenic

Biologic Fate

Asbestos bodies

Lower airways and alveoli

Pleural or peritoneal spaces or the
mesothelium

Asbestos bodies

Asbestos Exposure Pathways

Most common exposure pathway:

- Inhalation of fibers

Minor pathways:

- Ingestion

- Dermal contact

Populations At Risk - Asbestos - Current Exposures

Construction workers, mechanics
(brake pads)

People in homes with friable
asbestos materials

People in areas where asbestos
-bearing rock is disturbed

Populations At Risk - Asbestos - Past Exposures

Mechanics, construction workers,
shipyard workers, and military
personnel

Secondary exposure in the
workplace

Household contacts of workers

Asbestos: Types

Serpentine
(93% of commercial use)

Chrysotile
(7% of commercial use)

Actinolite, Amosite,
Anthophyllite, Crocidolite,
Richterite, Tremolite

Asbestos: Occurrence in the United States

Until 1975: Automobile, building
construction and shipbuilding
industries

Until 1990: Contaminant in vermiculite

Today: Exists in older homes and
commercial buildings

- problematic when loose, crumbling, or disturbed

Today: Still used in brake pads, clutches,
roofing material, vinyl tiles, and some
cement pipes

Naturally occurring asbestos is found in
parts of the U.S. areas in asbestos bearing
rocks. It is released:

- when disturbed
- as rocks weather

Asbestos: Description

Asbestos is a generic term for a group
of six mineral silicates

- Asbestos fibers are:

- Very strong

- Highly flexible

- Resistant to breakdown by acid, alkali,
water, heat, and flame

- Non-biodegradable

- Environmentally persistent

Asbestos - Learning Objectives

What is asbestos?

Most important route of exposure

Populations most heavily exposed

Diseases associated with asbestos
exposure

Common findings on medical evaluation

Chest radiograph findings

Pulmonary function test findings

Other tests that can assist with
diagnosis

Primary treatment strategies

Instructions for patients

Sunday, September 13, 2009

Prognosis

Mesothelioma patients prognosis in
large part depends on which type of
mesthelioma they have.
With the new drug Alimta and
chemotherapy, as well as surgery
mesothelioma patients are beginning to
live longer than they could have hoped
for in the past.

Surgery

Surgical removal is possible in some

cases but in many cases removal of the

tumor alone is not enough.

There are also many cases in which

surgery is not an option.

Side Effects

Alimta has also improved lung function

in many patients.

Side effect include low white blood cell

counts, vomiting, nausea, fatigue,

diarrhea, and rash.

However, taking folic acid and the

vitamin B12 helps reduce the intensity

of side effects.

Alimta

In a clinical study of 448 patients Alimta

was successful in increasing survival

time of patients by approximately 30%.

Alimta is administered in one ten

minute infusion every three weeks.

It has also shown great results in

conjunction with cisplatin, a standard

chemotherapy drug.

Treatments

Treatment options for all three types of

mesothelioma are the same.

Until recently there was no effective

treatment for mesothelioma.

A new drug, Alimta, was recently

approved by the FDA.

Mesothelioma Diagnosis

Since symptoms of mesothelioma,

which can include pain in the lower

back and shortness of breath, are often

mistaken for other problems,

mesothelioma is most frequently not

diagnosed until it is in an advanced

stage.

Types of Mesothelioma

Mesothelioma can be divided into three
different types.

Epithelioid- which has the best
prognosis out of the three types.

Sarcomatoid- which has about a 7 –
20% survival rate.

Mixed/biphasic- which has about a 20 –
35% survival rate.

Malignant Mesothelioma

Tumors found in the mesothelioma can
be both benign or malignant.
Malignant tumors are often called
malignant mesothelioma or just mesothelioma.

About the cancer

Mesothelioma is most often a cancer

associated with large amounts of

exposure to asbestos.

This cancer affects about 2,000 to

3,000 Americans every year.

Mesothelioma

Mesothelioma is a rare lung cancer that

begins in the mesothelium.

The mesothelium is made up of mesothelial

cells which line the chest and abdominal

cavities as well as the cavity around the

heart.

The mesotheiom also produces a lubricating

fluid that allows the organs to move easily.

Saturday, September 12, 2009

Major Route To Exposure To Asbestos

The major route of exposure to asbestos is
inhalation

There is no known “safe” level of exposure
Tightly bound asbestos poses no immediate
hazard

Asbestos becomes a health hazard when fibres
become airborne

Exposure should be minimised by sensible
precautions

What is a safe level of exposure to asbestos?

The level of exposure that may cause health
effects is not known.

It is therefore important to keep exposure to
asbestos fibres as low as possible and
precautions must always be taken.

What is the risk from a one off exposure?

The risk has not been quantified, but except for
intense exposures, the risk caused by brief
exposure is likely to be undetectably low..

Exposure to asbestos fibres in air

Small quantities are present in air breathed by
most people without developing asbestos-
related disease

People who have developed disease from
asbestos were exposed to workplace air levels
around 5 fibres/ml

Measured E in public buildings, schools

0.0001- 0.0005 fibres/ml.

Life-time E at this level < 1 in 100,000 life-
time cancer risk.

Mesothelioma

Pleural Mesothelioma

Malignant mesothelioma

Rapidly fatal : 75% dead 1 year after
diagnosis

Smoking has no apparent effect on risk

Symptoms: short of breath, chest pain,
weight loss

Has occurred in people without direct
occupational exposure but exposed to large
quantities of dust

Malignant mesothelioma

a cancer of the lining of the lung and chest
cavity (pleural mesothelioma) (2/3)

or the lining of abdominal cavity (peritoneal
mesothelioma)

can take 30 to 50 years to develop

particularly associated with crocidolite

Australia has world’s highest incidence

Lung Cancer Image

Cancer site, lymph glands

Lung cancer And Asbestos

usually takes 10 to 20 years to develop after
asbestos exposure.

asbestos in non-smokers: 5x background
rate

asbestos in smokers: 50x background rate

Symptoms: persistent cough, weight loss, cough up blood

Asbestosis Diseased Person

Asbestosis

A chronic and progressive lung disease
caused by inhaling asbestos fibres over a long
period of time.

5- 20 years to develop

inflammation from fibres causes scarring
(fibrosis) and stiffening of the lung. This
causes less oxygen exchange

Symptoms – short of breath, cough, chest tightness

Pleural plaques Image

Pleural plaques

Pleura: 2 layers of membrane line the chest
wall & cover the lungs

asbestos may produce thickened patches

is not cancerous but can affect lung function

generally no symptoms

indicates significant previous exposure

Common in occupational E & sometimes
where high environmental levels

Cancer

Lung Cancer

Asbestos related diseases

All forms of asbestos can potentially cause:
Non cancer
pleural plaques
asbestosis
Cancer
lung cancer
malignant mesothelioma

Asbestos

Exposure to Asbestos

What are the health effects of exposure to asbestos?

Asbestos becomes a health hazard when
fibres become airborne and are inhaled.

Effects depend on length, diameter and
composition of fibre

Disease is usually associated with long-term
exposure in occupational or para-occupational
setting (immediate family or live near asbestos
mine or factory)

Risk depends on how much and how long