Mesothelioma

What every physician needs to know:

Malignant pleural mesothelioma (MPM) is a rare locally invasive, lethal malignancy associated with asbestosis, which is difficult to diagnose and treat. Eighty percent of MPM is attributed to asbestos exposure. Approximately 2000-3000 cases/year are diagnosed in US. Life expectancy once diagnosed with MPM, without treatment, is less than 6 months.

Asbestos is the commercial name for a group of hydrated magnesium silicate fibrous materials; serpentine and amphibole are the two major types of Asbestos. Asbestos is still used with restriction in cement, ceiling tiles, brake linings, ship buildings.

MPM is subdivided into three main histological subtypes: epithelioid, biphasic/mixed and sarcomatoid. Histological subtype is an important prognostic factor and also dictates the therapy offered.

Most patients present with pleural effusion of unknown etiology; those who have a high suspicious for MPM and are potential surgical candidates should have a temporary pleural catheter placed (e.g., Pleurx) so as to optimize surgical options. Those patients with advanced disease or not appropriate for resection should undergo talc pleurodesis, once diagnosis is established.

Patients should be managed by a multidisciplinary team, in centers with experience in the treatment of MPM.

The only first-line chemotherapy approved by FDA is the combination of cisplatin and pemetrexed, based on a large (456 patients) phase III trial which showed improved OS with the combination versus single agent cisplatin.

Epithelioid tumors

Epithelioid tumors are the most common tumors accounting for 60% of mesothelioma subtypes. Epithelioid tumors have the best prognosis and are most likely to respond to chemotherapy. Differential diagnosis include reactive mesothelial hyperplasia and metastatic carcinomas. Reactive mesothelial hyperplasia can be caused by infections, connective tissue disease, drug reactions, surgery and trauma.

Sarcomatoid tumors

Sarcomatoid (malignant spindle cell) tumors are automatically classified as stage IV, generally considered nonoperable, and convey the worst prognosis. Differential diagnosis include mesenchymal tumors such as leiomyosarcoma and synovial sarcoma.

Are you sure your patient has malignant pleural mesothelioma? What should you expect to find?

Patients present with a latency of 20-60 years after exposure to asbestosis. Clinical picture: dyspnea, nonpleuritic chest pain and cough due to pleural effusion. Non-specific symptoms include fevers, night sweats, fatigue and weight loss.

Patients may also be asymptomatic and present with a chest wall mass, pleural effusion or other pleural pathology on imaging. However, up to 25% of patients have not had asbestos exposure, with their etiology of developing MPM unknown.

Tissue diagnosis is required. Histological subtyping has higher yield with surgical biopsy versus radiological guided biopsies.

Diagnosis

1) CT thorax with contrast

2) Thoracentesis

Cytology low diagnostic yield (20%).
Fluid usually exudative and hemorrhagic, but could be transudative and clear if there is less tumor burden.
Core needle/CT guided pleural biopsy (80% accuracy with immunostaining)
High rate of tract seeding; hard to prevent, but usually clinically inconsequential; if surgery is contemplated, the needle site can be resected.

3) Video-assisted thoracoscopic (VATS) (98% diagnostic rate) biopsy

Indications: need for more tissue for histologic subtyping; drainage of effusion; placement of pleural catheter or other mechanical pleurodesis method; determining extent of tumor involvement; drainage of pericardial effusion; biopsy of mediastinal lymph nodes.
Done under general anesthesia, one lung ventilation.
Can be done with 1-3 port sites.

4) Serum soluble mesothelin-related proteins (SMRP). These circulating peptides are not fully understood but may consist of fragments of mesothelin, or abnormal mesothelin that cannot bind to the membrane.

Beware of other conditions that can mimic malignant pleural mesothelioma:

Diagnosing MPM is not an easy task. Differentiating benign versus malignant pleural disease as well as distinguishing MPM from other malignancies might be impossible by pathology alone. The most important differential diagnosis to epithelioid MPM is metastatic adenocarcinoma with pleural effusion. Diagnosis is based on histology and immunohistochemical (IHC) staining, in stages.

Typically, IHC staining is positive for:

calretinin (sensitivity = 98%)
keratin 5 (sensitivity = 99%)
wilms tumor protein 1 (WT-1) (sensitivity = 98%)

Typically IHC staining is negative for:

carcionoembroyonic antigen (CEA)
thyroid transcription factor (TTF-1)

The panel is expanded if the results are discordant. If no diagnosis is obtained, gene expression profiling and electronmicroscopy might be utilized. Flow cytometry is not a useful diagnosing tool.

SMRP and osteopontin might also help with establishing diagnosis. SMRP has a sensitivity of 50-84% and specificity ranging between 72-95%. Although SMRP measurement is problematic, the FDA has approved MESOMARK (a commercial SMRP test), for epithelioid or biphasic disease monitoring. Osteopontin sensitivity for mesothelioma is only 47%, and this test lacks specificity. Benign disease such as inflammatory bowel disease can also cause an elevated osteopontin level.

Which individuals are most at risk for developing malignant pleural mesothelioma:

Asbestosis exposure is the major risk factor for MPM. The lifetime risk of MPM in people with asbestosis exposure ranges from 4.5% – 10%. Insulation workers are at greatest risk. Other occupational risk groups are carpenters, electricians, mining/milling, general ship yard, heating and construction workers.

Asbestos is still a hazard for about 1.3 million workers in the US. Due to latency, patients usually present between ages 50-70. More prevalent in men (5:1), secondary to the occupational link.

Radiation exposure to the chest wall is proposed to be a risk factor. There is conflicting data regarding radiotherapy for breast cancer, but data supports mesothelioma secondary thoracic radiotherapy in Nonhodgkins/Hodgkins lymphoma and testicular cancer.

Other proposed causative agents are Eritonite, which is an asbestos like fiber found in building material in Turkey, and Simian Virus 40 (SV40), a polyoma virus.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

1) CT chest/abdomen with contrast.

2) PET-CT for staging.

If considering surgical resection:

Pulmonary function tests (after effusion is drained, including FEV1, FVC, ABGs and DLCO).
Echocardiogram (ECHO) (to evaluate left and right heart function).
MUGA scan (to evaluate right and left heart function if unable to by ECHO).
Quantitative ventilation/perfusion scan.

Optional other studies:

Mediastinoscopy or endobronchial ultrasound (EBUS) biopsy of mediastinal lymph nodes.
Laparoscopy to rule out transdiaphragmatic exension.
VATS to evaluate extent of disease, to ascertain more tissue for histologic diagnosis, and to exclude suspicion of contralateral disease.
MRI chest to exclude vascular and/or diaphragmatic involvement.

Staging

See Table I. TNM staging of mesothelioma.

What therapies should you initiate immediately i.e., emergently?

In cases of severe shortness of breath and large pleural effusions, thoracentesis for symptom control. If the effusion recurs, repeated thoracentesis is reasonable. If the patient has potentially resectable disease, a pleural catheter should be placed. If the disease is not surgically resectable, then talc pleurodesis should be performed to minimize effusion recurrence.

What should the initial definitive therapy for the cancer be?

Patients need to be evaluated by a multidisciplinary team including medical oncology, thoracic surgery and radiation oncology. A small select group of patients, with stage II or III disease and good performance status can be evaluated for trimodal therapy.

If specific histologic cell type has not been determined, then a VATS pleural biopsy should be done. This would also help to determine the extent of disease and whether the visceral pleura involved would require an extrapleural pneumonectomy.

Clinical stage I-III (epithelial or mixed histology) – Surgical evaluation
Clinical stage IV or sarcomatoid histology – These scenarios are considered unresectable and are treated with chemotherapy

Operable

Stage I: Surgical resection

Stage II-III: Trimodality therapy

There is considerable debate regarding indications for and types of surgical procedures.

The two major approaches to surgery are:

Extrapleural pneumonectomy (EPP): en bloc resection via major thoracotomy of the involved pleura, lung, diaphragm and pericardium. The pericardium and diaphragm are usually reconstructed with synthetic or biologic material. This is extensive surgery associated with high morbidity (22-37%) and mortality (4-15%).
Pleurectomy/Decortication (P/D): complete removal of the involved pleura and all gross tumor, leaving the lung intact. Mortality with this procedure is lower (3-7%).

Both operations are extremely complex and should be done by experienced general thoracic surgeons.

A large retrospective analysis (667 patients) compared EPP to P/D, showing that P/D had improved overall survival and decreased adverse outcome compared to EPP. Many patients are unable to complete trimodality therapy with EPP and an evolving thought is that if P/D rather than EPP is incorporated in trimodality therapy more patients might be able to complete adjuvant treatment.

Trimodality therapy consists of incorporating neoadjuvant or adjuvant chemotherapy, surgery and adjuvant radiation therapy. Studies support the safety and feasibility of neoadjuvant chemotherapy, followed by surgery and then adjuvant radiation.

Medically inoperable

Chemotherapy

Unresectable malignant pleural mesothelioma

Most cytotoxic agents have been evaluated in mesothelioma. Few drugs have consistently yielded response rates over 20%. Evaluating the supporting data for treatment options is difficult because of the following:

There are few randomized trials due to the small number of patients with this diagnosis.
Response criteria and measurements are not standardized.
Histologies are heterogeneous in clinical trials.
Staging is not standardized in clinical trials.

First-line regimens

Pemetrexed 500 mg/m² day 1 + cisplatin 75 mg/m² day 1 every 3 weeks.
Pemetrexed 500 mg/m² day 1 + cisplatin 75 mg/m² day 1 + bevacizumab 15 mg/kg day 1 every 3 weeks for 6 cycles followed by bevacizumab maintenance until progression or unacceptable toxicity.
Pemetrexed 500 mg/m² day 1 + carboplatin AUC 6 day 1 every 3 weeks (if unable to tolerate cisplatin).
Gemcitabine 1000 mg/m² IV on day 1, 8, 15 and cisplatin 80-100 mg/m² IV on day 1 of a 28 day cycle.
Pemetrexed (500 mg/m² on day 1 every 3 weeks).
Vinorelbine (30 mg/m² IV once weekly in a 6 week cycle).

Second-line regimens

No Second-line treatment is standard of care or FDA approved.

Pemetrexed 500 mg/m²on day 1 every 3 weeks (if not given as first-line therapy).
Vinorelbine (30 mg/m²IV weekly in a 6 week cycle).
Gemcitabine (1250-1500 mg/m² IV on day 1, 8, and 15 of a 4 week cycle).

What other therapies are helpful for reducing complications?

Pleural (Pleurx) catheter
Thoracentesis
Talc pleurodesis
Partial pleurectomy and/or decortication
Radiation, which can be used both as part of trimodality therapy and palliation for metastasis in bone and chest wall. Radiation can also be used to prevent tumor seeding of catheter tracts and surgical incisions.
Photodynamic therapy (should be done within a clinical trial)
Antiemetics with cisplatin-based chemotherapy

What should you tell the patient and the family about prognosis?

MPM is a very difficult to treat, largely fatal and a rarely curable disease with a median overall survival of 9-17 months. Surgical resection is only possible in a small select group of patients. Goal of therapy is often palliative. Combination chemotherapy with cisplatin and pemetrexed can improve survival by 3 months. Clinical trials should be considered, since cure rate with standard therapy is low and optimal combination of therapeutic modalities is not clear.

What if scenarios.

Be aware of complications by local invasion leading to dysphagia, hoarseness, cord compression, brachial plexopathy, Horners Syndrome, SVC syndrome.
Distant metastatic disease is rare, but can occur.
Contralateral pleural or intra-abdominal involvement.
Assess pulmonary reserve prior to surgery. Generally when considering EPP, predicted post-operative FEV1 should be more than 800cc or 30% of predicted; DLCO should be over 40%; CO2 should be under 50 mm Hg.
Establish diagnosis prior to talc pleurodesis.
If talc pleurodesis is performed, and surgical resection is contemplated, the pleural fusion from the talc relegates the need to do an EPP due to technical considerations. Similarly, if the visceral pleura is spared of tumor at the time of VATS examination, then a pleurectomy/decortication can be a surgical option.
Patients who have stable disease after induction chemotherapy: surgical resection can be offered depending upon the comorbidies of the patient.

Follow-up surveillance and therapy/management of recurrences.

CT chest/abdomen with contrast to evaluate for response to therapy.
PET-CT can be considered to evaluate for response to neoadjuvant therapy.
SMRP can be used to evaluate for recurrence. SMRP levels can be followed after surgical resection at the time of routine radiologic assessment. Rising levels of SMRP can be correlated with radiologic recurrence.
It is reasonable to perform surveillance at intervals established for more common thoracic malignancies such as lung cancer: for definitively treated early stage disease–imaging every 6-12 months for 2 years, then yearly. For advanced disease treated with chemotherapy–every 2-3 cycles to assess response.
Surgical re-resection could be offered for recurrence if amenable to simple excision.

Pathophysiology

Eighty percent of MPM arises from the mesothelial lining of the parietal pleura. It is specifically unknown how asbestos induces MPM at the molecular level. However, several genetic pathways have been defined including the involvement of tumor suppressor genes such as p16, p14, and p53. Also, expression of growth factors and receptors such as TGF-alpha, IGF, PDGF and HGF have been identified.

What other clinical manifestations may help me to diagnose malignant pleural mesothelioma?

History

Dyspnea, Non pleuritic chest pain, cough, chest wall pain, weight loss, fever, night sweats and fatigue

Physical exam

Unilateral pleural effusion, decreased breath sounds, dullness to percussion at the lung bases, egophony and palpable chest wall masses. This particularly in patients with a history of known exposure to asbestos, or previously healthy person without major medical issues.

What other additional laboratory studies may be ordered?

CMP
LDH
PTH rP (if calcium is elevated)
CBC with differential, thrombocytosis, leucocytosis and anemia indicates poor prognosis.

Paraneoplastic syndromes: DIC, migratory thrombophebitis, coombs positive hemolytic anemia, hypoglycemia, hypercalcemia.

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.

Jump to Section

Imaging