Definition and History

The term was first used in 1921 by Eastwood & Martin to describe primary tumors of the pleura

• At that time, the diagnosis was extremely controversial (required autopsy examination)

• Today, the diagnosis is still problematic

• • 15 % of cases can not be differentiated from adenocarcinoma

• 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: Expected Peak, 2010 - 2020 (2,700 - 9,000 deaths/yr.)

  • U.S. Experience: Peaked in the 1970's & since 1980 the incidence has been decreasing

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 respond

• Effect on third-world countries

• 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

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

Cases due to exposure in buildings with asbestos insulation are extremely rare !

The Risk

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

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

There has never been prospective evidence to support the widespread removal of asbestos insulation...

3 Main Groups:

• Benign Localized Mesothelioma

• • “pleural fibroma”

  • Unassociated with asbestos exposure

  • Paraneoplastic syndromes occur in 1/3

  • • Migrating Thrombitis

    • Thrombocytosis

    • Hemolytic Anemia

    • Hypoglycemia

    • Hypercalcemia

    • Pulmonary Hypertrophic Osteoarthropathy [Boutin 1998]

  • Arise from the visceral pleura

  • Unless incomplete, surgical resection is curative

• 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 approaches MDM

    • External beam radiation is of little benefit

• 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 Scenario

Middle-aged man with pleuritic chest pain, shortness of breath, & a clear history of asbestos exposure

3 Cell Types:

Pathogenecity:

Clinical Points:

Diagnostic Work-Up

• CXR (with thoracentesis)

• Chest C.T.

• • irregular, nodular pleural thickening

  • spread into the diaphragm, pericardium, chest wall, or mediastinal lymph nodes is difficult to assess [Masilta 1991]

• Thoracoscopy with Biopsy

• MRI

Staging

• Stage I : tumor isolated to ipsilateral pleura or lung

• Stage II: tumor invades chest wall, mediastinum, pericardium, or contralateral pleura

• Stage III: tumor involves both thorax & abdomen

• Stage IV: distant blood-borne metastases

Expected Survival:

Establishing the Diagnosis

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

• Cardinal Characteristics

• • Age between 55 – 65

  • Previous occupational exposure to asbestos

  • Pleural Effusion

  • C.T. / MRI (with nodular lesions of the parietal pleura) [Boutin 1998]

• VATS

• • 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

  • 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

  • 98 % sensitive in establishing the diagnosis

  • Mortality is 1:8000

  • Complications are minimal

  • • Subcutaneous Emphysema

    • Localized Infection

    • Minor Bleeding (< 100 cc)[Viallat 1991]

  • 1 Problem with VATS: Seeding of the Trocar Path

  • • unknown incidence but can occur

    • has been documented after thoracentesis & blind pleural biopsy

Can be prevented by performing Prophylactic Radiotherapy after healing to the point of entry [Rey 1995]

Natural History

• Median Survival : 12 - 17 months

• 5-year Survival : < 5 %

• Mesothelioma is a Local Disease

• • Invasion usually first involves the Lung & Diaphragm

  • • Progressive Retraction of the hemithorax leading to a “trapped lung”

    • Peritoneal Infiltration - through the diaphragm or it's posterior openings with secondary ascites

• Spread to the Endothoracic Fascia (T2) or Intercostal Spaces (T3) is common

• • Found in 30 - 50 % of patients at the time of biopsy[Chahinian 1983]

  • Parietal involvement can be “massive”

  • UNCOMMON:

  • • Clinically-detectable lesions in bone, tissue, or brain

    • Involvement of the contralateral lung

However, at the time of autopsy, 50 % of patients will have metastatic spread [Antman 1981]. Death is usually due to progressive dyspnea & respiratory insuffiency with extensive weight loss & muscle wasting

There is no single treatment which has proven effective...

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; 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 %

• 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 %

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 1998]Aisner 1995

• • The only prospective study

  • Pneumonectomy, w/o post-operative treatment

  • • 2-yr. Survival: 33 %

    • Median Survival: 10 months

A prospective, randomized, phase III trial is required to find the appropriate role of surgery.

Treatment: Radiation

Treatment: Chemotherapy

Responses seen in 20 -30 % of patients, but without improvement in overall mortality

Treatment: 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 1995]

Summary

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)

• 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

south african miners -

european industrialists -

american manufacturers -

slowly but effectively...