Mesothelioma

Diagnosis

Indications for Testing

  • High suspicion for mesothelioma – includes abnormal chest x-ray (pleural effusion, pleural plaques)
  • History of asbestos exposure with clinical case suspicion (not necessary for diagnosis)

Laboratory Testing

  • Serum testing – not useful in diagnosis

Histology

  • Diagnosis is based on combination of appropriate histology and immunohistochemistry (IHC) on adequate biopsy in conjunction with clinical surgical and radiographic history (2013 Consensus International Mesothelioma Interest Group)
    • Consultation with a specialist is recommended
    • Guidance on evaluation of possible malignant mesothelioma varies across medical literature
  • Tissue specimens required for diagnosis
    • Body cavity fluid cytology
      • May be negative – not usually diagnostic
      • Not all patients with mesothelioma develop effusions
    • Pleural biopsy – CT-guided or thorascopic video-assisted thoracic surgery biopsy, Abrams needle
    • Open thoracotomy – use only if less invasive testing not diagnostic
  • Immunohistochemistry
    • Role depends on
      • Histologic subtype (epithelioid vs. sarcomatoid vs. desmoplastic variant of sarcomatoid)
      • Location (pleural vs. peritoneal)
      • Differential diagnosis
      • Most useful in initial workup to use 2 mesothelial markers and 2 markers for suspected other tumor(s)
    • IHC staining may be chosen by subtype of pathology
      • Morphologic assessment performed first with IHC as adjunct testing
      • Acceptable method – use 2 markers for mesothelioma and 2 for suspected carcinoma cell type
      • Add markers based on initial marker pattern in a stage-wise approach if testing combination yields no definitive answer
    • Reactive mesothelial hyperplasia vs. malignant mesothelioma distinction is critical

      Antibody

      Reactive Mesothelium (% positive)

      Mesothelioma (% positive)

      EMA

      20%

      80%

      p53

      0%

      45%

      IMP3

      0%

      73%

      GLUT-1

      3%

      67%

      Desmin

      85%

      10%

      Source: International Mesothelioma Interest Group, 2012

    • IHC for differentiating epithelial pleural mesothelioma from other lung tumors

      Mesothelioma

      Adenocarcinoma – lung

      Squamous cell carcinoma – lung

      • Calretinin
      • Cytokeratin 5, 6 (CK 5,6)
      • WT-1
      • D2-40
      • Epithelial-related antigen (MOC-31)
      • BG-8 (Lewisy)
      • Carcinoembryonic antigen (CEA) monoclonal
      • B72.3
      • Ber-EP4
      • TTF-1
      • Napsin A
      • p63 or P40
      • MOC-31
      • BG-8 (Lewisy)
      • Ber-EP4
    • IHC for differentiating epithelial pleural mesothelioma from other tumors

      Melanoma

      Lymphoma (large cell)

      Angiosarcoma

      Metastatic breast cancer

      Metastatic renal cell

      • S-100
      • HMB45
      • CD45
      • CD20
      • CD3
      • CD30
      • CD31
      • CD34
      • Estrogen receptor (ER)
      • Mammaglobin
      • Gross cystic disease fluid-protein 15 (GCDFP-15)
      • PAX8 or PAX2
      IHC for differentiating epithelioid peritoneal mesothelioma from other tumors

      Mesothelioma

      Papillary serous carcinoma

      Nongynecologic adenocarcinoma (eg, gastric)

      • Calretinin
      • D2-40
      • WT-1
      • MOC-31
      • PAX8
      • BG-8
      • Ber EP4
      • MOC-31
      • BG-8
      • CEA
      • B72.3
      • Ber EP4
      • CDX2
      IHC for differentiating sarcomatoid peritoneal mesothelioma from other tumors

      Mesothelioma

      Sarcoma/melanoma/lymphoma

      • Cytokeratin – use multiple such as AE1,3;  CAM 5.2; and CK 7
      • D2-40
      • Calretinin
      • CD31
      • CD34
      • Desmin
      • Myoglobin
      • S-100
      • CD45
  • Molecular markers – homozygous deletion of qp21 locus; p16/CDKN2A deletions most often in pleural subtypes
    • IHC p16 positivity does not translate to molecular deletion

Imaging Studies

  • CT (with contrast)/MRI for initial evaluation of abnormal chest x-ray

Differential Diagnosis

  • Pleural
    • Fibrous pleurisy secondary to a variety of inflammatory causes (eg, infections, collagen vascular diseases, pulmonary infarcts, trauma, surgery, drug reactions)
  • Malignancy
  • Other – solitary fibrous tumor, pleural epithelioid hemangioendothelioma
  • Peritoneal

Screening

  • Imaging (CT/x-ray/MRI) – not recommended on a regular basis for screening or monitoring of asbestos-exposed workers
  • Serum biomarkers – no proven efficacy in screening of asbestos-exposed workers
  • Screening studied in high-risk patients (those with asbestos exposure) – no guidelines currently recommend screening for malignant pleural mesothelioma

Monitoring

  • Soluble mesothelial-related peptides (Mesomark)
    • Useful for monitoring epithelial or biphasic mesothelioma
    • Requires serial measurement
    • Not useful as a diagnostic test

Clinical Background

Mesothelioma is a rare malignancy involving the serous lining of body cavities, including pleura (most common), peritoneum, pericardium, tunica vaginalis testis in men, or tunica serosa uteri in women.

Epidemiology

  • Incidence
    • 1-2/100 million – 2,500 new cases each year in U.S.
    • Increasing incidence in Russia, Western Europe, China, India
    • Increasing incidence in males ≥75 years
      • No increase in U.S. males or females <75 years – coincides with OSHA asbestos restrictions
  • Age
    • 72 – median
    • Maximum lifetime risk for developing mesothelioma – individuals born 1925-1929
  • Sex – M>F; 5:1
    • Maximum lifetime risk for mesothelioma in males occurs in the 1925-1929 birth cohort – due to highest rate of asbestos exposure

Risk Factors

  • Asbestos exposure – amphiboles more carcinogenic than chrysotile fibers
    • 70-80% of mesothelioma cases occur in patients with history of asbestos exposure
    • At-risk occupations include shipbuilding, construction (ceiling tiles and boilers, especially prior to 1970), fireproofing, automobile brakes and clutches
  • Genetics
    • Chromosome deletions (1p, 3p, 9p, 6q)
  • Pathophysiology

  • Malignant pleural mesothelioma (MPM)
    • 3 histological types
      • Epithelioid – 50-60%
      • Biphasic (or mixed) – 25-35% 
      • Sarcomatoid – 10-20%
    • May be mistaken for adenocarcinoma of the lung; histologically heterogeneous tumors
      • Histology affects survival
    • Long latency period (30-50 years) between asbestos exposure and disease development
      • Not all mesotheliomas are related to asbestos exposure, and the absence of an asbestos exposure history does not exclude the diagnosis
    • Asbestos fibers are mutagenic and carcinogenic to several cells – commonly found in excised tumors
  • Peritoneal malignant mesothelioma (PMM)
    • Less likely to be related to asbestos exposure
    • Malignant
  • Benign multicystic mesothelioma – well-differentiated
  • Papillary mesothelioma – well-differentiated

Clinical Presentation

  • Disease usually advanced at time of presentation
    • Pleural – dyspnea, nonpleuritic chest pain, pleural effusion, cough, fatigue
    • Peritoneal – abdominal pain, ascites, anorexia, bloating, blood clotting abnormalities, anemia
    • Pericardial – chest pain, constrictive pericarditis

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cytology, Body Cavity Fluid 8209701
Method: Microscopy

May aid in the diagnosis of mesothelioma

   
Pan Cytokeratin (AE1,3) by Immunohistochemistry 2003433
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Cytokeratin 7 (CK 7) by Immunohistochemistry 2003854
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Cytokeratin 20 (CK 20) by Immunohistochemistry 2003848
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Cytokeratin 5,6  (CK 5,6) by Immunohistochemistry 2003851
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Wilms Tumor (WT-1), N-terminus by Immunohistochemistry 2004184
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Calretinin by Immunohistochemistry 2003490
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
HBME-1 (Mesothelial Cell) by Immunohistochemistry 2003914
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
D2-40 by Immunohistochemistry 2003857
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Keratin 903 (K903) High Molecular Weight by Immunohistochemistry 2003978
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Thyroid Transcription Factor (TTF-1) by Immunohistochemistry 2004166
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Carcinoembryonic Antigen, Monoclonal (CEA M) by Immunohistochemistry 2003824
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Breast Carcinoma b72.3 by Immunohistochemistry 2003445
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Anti-Human Epithelial Antigen, Ber-EP4 by Immunohistochemistry 2003463
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
CD15, Leu M1 by Immunohistochemistry 2003529
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

   
Soluble Mesothelin Related Peptides (MESOMARK®0081284
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Monitor mesothelioma

Not a diagnostic test

Humanitarian-use device; requires IRB approval for use

Requires serial measurements

Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Cytology, Pulmonary 8209702
Method: Microscopy

Aid in the diagnosis of mesothelioma

Epithelial-Related Antigen, MOC-31 by Immunohistochemistry 2003875
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed

E-Cadherin by Immunohistochemistry 2003869
Method: Immunohistochemistry

Aid in histologic diagnosis of mesothelioma

Stained and returned to client pathologist; consultation available if needed