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 (To order, use Test code 2000623, NG REQUEST) 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 (To order, use Test code 2000623, NG REQUEST) 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