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Malignant Mesothelioma

❓What❓

  • Cryptic “serosal” malignancy owing to its insidious onset, diverse sites of mesothelial origin, & context/pathologic challenges in diagnosis

❓Epidemiology❓

“Mesothelioma” 🌎

  • ~85% pleural (~3300 cases/yr in USA)
  • ~10-15% peritoneal (~600 cases/yr in USA)
  • ~1% pericardial, <1% testicular

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Risk Factors ☝️

  • Asbestos (any location i.e. not just pleural)
  • Smoking
  • s/p Radiation therapy
  • Recurrent serositis
  • Genetic (i.e. BAP1 carriers)

Histology, Subtypes 🔬

  • Epithelioid (most common, best prognosis)
  • Sarcomatoid (less common, worst prognosis)
  • Biphasic (elements of both )

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a, Cell block preparation from a pleural effusion showing clusters of atypical mesothelial cells and inflammatory cells. b, Epithelioid mesothelioma with relatively uniform cells containing moderate cytoplasm, forming papillary structures with fibrovascular cores. c, Sarcomatoid mesothelioma with spindle cells showing varying degrees of nuclear atypia (the less atypical areas especially in the centre of the field would be called desmoplastic component). d, Biphasic mesothelioma with sarcomatoid (top) and epithelioid (bottom) components. Note chondrosarcomatous differentiation in the sarcomatous component, which is not known to have any clinical significance. e, Immunohistochemical staining shows BAP1 deletion in tumour cells; positive normal cells in stroma, which serve as internal control. f, Immunohistochemical staining shows MTAP deletion in a cytological preparation of pleural effusion. Cells staining positive are coloured brown.

❓Presentation❓

Tempo 🦀

  • Latency period of ~30-50 years (exposure → mutation) means vast majority of patients are older than 60

  • Insidious spread means patients typically present with advanced disease

    • Clinical 🦀

  • Pleural: lower respiratory symptoms due to recurrent exudative effusion (”epithelioid”) vs. isolated pleural disease without effusion (”sarcomatoid”)*

⚪ ”Effusion” presentations are more common owing to the epidemiology of the more common “epithelioid” subtype, which generally sheds cells into the serosal space. (This stands in contrast to the ”sarcomatoid” subtype, which does not usually cause such shedding: this distinction has implications for the optimal path to diagnosis.)

  • Peritoneal: gastrointestinal symptoms due to metastatic spread* (peritoneal carcinomatosis, recurrent ↓ SAAG ascites due to lymphatic spread) > primary peritoneal disease

⚪ Given many patients with pleural mesothelioma present with advanced disease, peritoneal symptoms may overtake pleural symptoms & shift the diagnostician’s eyes away from the intrathoracic space, thus presenting a major context challenge

Radiographic 🦀

  • Pleural
    • Pleural abnormality, ⊕ Effusion (“epithelioid”)
    • Pleural abnormality, ⊖ Effusion (“sarcomatoid”)
    • Pleural plaques and/or Calcifications (surrogate evidence)

“There is a mild to moderate loculated right pleural fluid collection. There are both visceral & parietal pleural calcifications in this area. There is a thin curvilinear strip of adjacent basilar right airspace disease favoring compressive atelectasis and/or scarring. Small pleural calcifications are also identified along the right major fissure. There is no left pleural fluid collection.”
“There is a mild to moderate loculated right pleural fluid collection. There are both visceral & parietal pleural calcifications in this area. There is a thin curvilinear strip of adjacent basilar right airspace disease favoring compressive atelectasis and/or scarring. Small pleural calcifications are also identified along the right major fissure. There is no left pleural fluid collection.”

  • Peritoneal
    • Ascites ⊕ peritoneal enhancement ⊕/⊖ thickening (”concerning for peritonitis”)

“Ascites with fat stranding & areas of thin peritoneal enhancement raise the question of peritonitis.”
“Ascites with fat stranding & areas of thin peritoneal enhancement raise the question of peritonitis.”

  • Pericardial
    • TTE: “effusive” (pericardial effusion), “constrictive” (e.g. RV/RA dilatation, prominent septal bounce, exaggerated respiratory variation in transmitral flows, expiratory diastolic flow reversal in hepatic vein)
    • CMR: pericardial thickening, enhancement, loculations

CMR showing marked pericardial thickening; enhancement of the pericardium after administration of contrast indicated pericardial fibrosis & inflammation (Panel A). The pericardium appeared to be markedly edematous on T2-weighted imaging (Panel B, arrow, fat-suppressed T2-weighted fast spin echo image). A loculated pericardial effusion (arrow) was adjacent to & compressing laterally a severely dilatated right atrium (RA) (Panel C). The structure posterior to the left atrium (asterisk) was interpreted to represent a collapsed lung with surrounding pleural effusion. Late gadolinium enhancement (Panel D) showed increased late gadolinium enhancement in both the parietal pericardium (yellow arrow) & visceral pericardium (red arrow), findings consistent with pericardial inflammation. Ao = aorta, LV = left ventricle, RV = right ventricle.
CMR showing marked pericardial thickening; enhancement of the pericardium after administration of contrast indicated pericardial fibrosis & inflammation (Panel A). The pericardium appeared to be markedly edematous on T2-weighted imaging (Panel B, arrow, fat-suppressed T2-weighted fast spin echo image). A loculated pericardial effusion (arrow) was adjacent to & compressing laterally a severely dilatated right atrium (RA) (Panel C). The structure posterior to the left atrium (asterisk) was interpreted to represent a collapsed lung with surrounding pleural effusion. Late gadolinium enhancement (Panel D) showed increased late gadolinium enhancement in both the parietal pericardium (yellow arrow) & visceral pericardium (red arrow), findings consistent with pericardial inflammation. Ao = aorta, LV = left ventricle, RV = right ventricle.

❓Diagnosis❓

Cytology: Foundational Knowledge 🛑

  • Sensitivity = volume dependent*

  • Histologic subtype = key (i.e. “sarcomatoid” does not shed)

⚪ ↑ volume = ↑ fluid to spin down = ↑ pellet size for analysis. (This is the basis for why cytology sensitivity for malignancy for CSF fluid <<< pleural/peritoneal fluid.)

⚪ Mesothelial cells are “sensitive” because they shed from the mesothelial lining into the serosal cavity as a result of any pathologic process resulting in effusions/ascites containing “reactive mesothelial cells” (i.e. inflammatory, traumatic), & they can be considered “chameleons” because their morphologic appearance is extremely variable (i.e. can be so floridly “atypical” that they mimic malignancy mesothelioma vs. false ⊖ due to lack of florid atypia)

Diagnostic Journey 🗻

  1. Correct context? (i.e. don’t let highly atypical mesothelial cells fool you)

  1. Fluid cytology vs. Tissue? (i.e. “sarcomatoid” will require biopsy of “rind”)

  1. Fluid cytology, request immunostaining*

  1. Tissue biopsy (thoracoscopy vs. laparotomy vs. nodal)

⚪ Since mesothelial cells are “sensitive chameleons,” immunostaining is needed to not only confirm the lineage of cells as mesothelial (e.g. calretinin, WT1, CK5/6), but also to assess for genetic changes highly suspicious for malignancy (loss of BAP1, loss of MTAP). This step is crucial for ensuring morphologically unimpressive “reactive mesothelial cells” do not terminate the diagnostic journey:

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📚 References 📚