Mesothelial cytopathology

Benign mesothelial cells from a pleural fluid specimen. (WC)

Adenocarcinoma (lung) and benign mesothelial cells in a pleural fluid specimen. (WC)

Mesothelial cytopathology is a large part of cytopathology. The article deals with cytopathology specimens from spaces lined with mesothelium, i.e. it deals with pericardial fluid, peritoneal fluid and pleural fluid.

An introduction to cytopathology is in the cytopathology article.

A general differential diagnosis of pleural effusion is given in the pleural effusion article.

Pleural fluid, pleural cytopathology, peritoneal fluid, and peritoneal cytopathology redirect to here.

Overview

• Sensitivity moderate for malignancy (60%).

Specimen types

• Wash, e.g. peritoneal wash: expect sheets of (benign squamous) cells.
• Spontaneous, e.g. pleural fluid: usually no large sheets.

Note: This distinction is important as wash specimens may have pseudopapillae.

Approach

Look for:

1. Two cell populations.
2. Large dark objects.
3. Boerner's red flags.

Boerner's red flags:

1. 3-D clusters.
   • Doublet & triplets common.
   • Quads-to-Quints - sweat breaks-out.
   • Sextuplets... very nervous.
2. "Busy" slide:
   • Nuclear pleomorphism.
   • Too many "intermediate cells".
   • Mitoses - 1-2/slide is "many".
3. Vacuolated cytoplasm.
4. Small cells with high NC ratio.

Features of malignancy

Strongly suggestive of malignancy:

• 3-D clusters.
• Large clusters.
• Highly cellularity.
• Irregular nucleoli.
• Group pleomorphism.

May be suggestive:

• High NC ratio.

Differential diagnosis

• Adenocarcinoma not otherwise specified (NOS) - most common.
• Reactive mesothelium.
• Malignant mesothelioma.
• Serous carcinoma.
• Lymphoma.

Less common:

• Squamous carcinoma.
• Rheumatoid pleuritis.
• Systemic lupus erythematosus pleurisy.
• Endosalpingiosis.
• Endometriosis.
• Small cell carcinoma.

Peritoneal cavity specific

• Hepatocellular carcinoma (HCC) may be associated with ascites... but it is rarely positive for malignant cells.
  • HCC in ascites fluid is super rare -- I haven't seen a case.

Normal mesothelium

General

Often seen in the context of:

• Gynecologic surgeries - done to exclude malignancy.
• Taps for ascites.

Cytology

Features:

• "Window" or "space" between attached cells (due to microvilli).
• Cytoplasmic blebs.
  • Bleb = "drop" of cytoplasm at cell periphery.
• +/-Multinucleated.
• Variable size (normal).
• Nucleoli (in reactive cells).

Note - abnormal features:

• Large clusters of cells, e.g. 150+ micrometres.

Images

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  Peritoneal wash - benign mesothelial cells in sheets (WC)

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  Peritoneal wash - benign mesothelial cells in sheets - high mag. (WC)

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  Pairs of mesothelial cells with an intercellular window. (WC)

Reactive mesothelium

General

• May be due to any number of causes.
• Can be severe in the context of (peritoneal) dialysis.

Cytology

See mesothelioma.

Images

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  PF - high mag. (WC)

• 

  PF - very high mag. (WC)

• 

  PF - very high mag. (WC)

Sign out

Pleural Fluid, Right, Thoracentesis: 
- Negative for malignant cells. 
- Reactive mesothelial cells present in a background of abundant lymphocytes. 

Comment: 
Additional sampling should be considered within the clinical context. 

Specific diagnoses - benign

Eosinophilic pleuritis

General

This has a large DDx:

• Trauma with air in the pleural cavity.
  • Repeated tap in the context of pneumothorax.
• Pulmonary infarct.
• Pneumonia.
• Parasitic infections.
• Hodgkin lymphoma.
• Idiopathic - most common cause.

Cytology

Features:

• Eosinophils >10%.

Rheumatoid pleuritis

General

• History of rheumatoid arthritis.
• Cytologic appearance considered to be pathognomonic.

Cytology

Features:

• Large (single) multinucleated cells - classically spindled.
  • May have epithelioid morphology.
• Necrotic debris - fluffy orange-to-blue crap.

Note:

• Necrotizing granulomatous inflammation.

Systemic lupus erythematosus pleurisy

Main article: Systemic lupus erythematosus

• AKA systemic lupus erythematosus pleuritis.

General

• Not common.
• Distinctive cytology.

Cytology

Features:

• Lupus erythematosus cells, usually abbreviated LE cells:
  • Pink blobs (representing a denatured nuclei) - phagocytosed by a neutrophil.

Image:

• LE cell (utah.edu).
• LE cell (tabers.com).

Specific diagnoses - malignant

Malignant mesothelioma

Main article: Malignant mesothelioma

General

• Can be challenging to diagnose.
  • NC ratio may be normal in mesothelioma.
  • Large NC ratios may be seen in reactive mesothelial cells.
  • Focal hyperchromasia is seen in reactive mesothelial cells.
  • Focal macronucleoli are seen in reactive mesothelial cells.

Cytopathology

Features:

1. Nuclear membrane irregularies (rare).
2. Hyperchromasia - diffuse.
3. 3-D clusters of cells (strongly suggestive).
   • Clusters of cells with "knobby" border; border is hobnail-like.
4. Large clusters of cells; >10 cells in a cluster (rare in benign).
5. Large NC ratio (common - not specific).
6. Gigantic cells; cells 2X+ neighbouring mesothelial cell (uncommon - but strong).
7. Nucleoli:
   • Macronucleoli - must be widespread (not common - strong).
   • Multiple nucleoli.
   • Irregular nucleoli (strong).

Notes:

• Single cells/small clusters - suggestive of mesothelioma vs. serous carcinoma. (???)

Mesothelioma versus reactive mesothelium:

Characteristic	Reactive mesothelial cells	Mesothelioma
Architecture	Flat sheets	3-D groups
Group size	Small, <10 cells	Large, >10 cells
Nuclear atypia - see Note 1.	+/-Hyperchromasia, +/-focal atypia	+/-Widespread atypia
Large cells	+/-Yes	No
Nucleoli	Common - small, focal large	+/-Large widespread, +/-multiple

Note 1:

• Best assessed on single cells.

Images

www:

• IHC mesothelioma (acta-cytol.com).
• IHC mesothelioma (nature.com).

• 

  Mesothelioma - 1 (WC)

• 

  Mesothelioma - 2 (WC)

IHC

• Calretinin +ve.
• WT-1 +ve.
• D2-40 +ve.
• TTF-1 -ve.
• CEA -ve.
• p63 -ve.

Adenocarcinoma

General

• Diagnosis represent a large number of distinct entities - see adenocarcinoma NOS.

Cytology

Adenocarcinoma in fluid - features:

• Classically large morules (clusters of cells that are heaped/are "3-dimensional"), known as cannonballs, with "community borders".
  • "Community border" = smooth, low surface area border; should be differentiated from a "knobby" border seen in mesothelioma.
• Intracytoplasmic "lumens"/inclusions (think lobular carcinoma).

DDx of cannonballs:

• Breast.
• Ovary.
• Lung.
• GI.

Images

Case 1

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  Adenocarcinoma - high mag. (WC)

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  Adenocarcinoma - very high mag. (WC)

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  Lung adenocarcinoma - high mag. (WC)

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  Lung adenocarcinoma - very high mag. (WC)

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  Lung adenocarcinoma - high mag. (WC)

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  Lung adenocarcinoma - very high mag. (WC)

Case 2

• 

  Adenocarcinoma - high mag. (WC)

• 

  Adenocarcinoma - very high mag. (WC)

• 

  Adenocarcinoma - very high mag. (WC)

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  Adenocarcinoma - TTF-1 - high mag. (WC)

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  Adenocarcinoma - TTF-1 - very high mag. (WC)

IHC

Breast:

• ER +ve/-ve.
• Calretinin -ve.

Colon:

• CK20 +ve.
• CDX2 +ve.
• Calretinin -ve.

Lung:

• TTF-1 +ve.
• Calretinin -ve.

Colorectal adenocarcinoma

Main article: Colorectal adenocarcinoma

• May be abbreviated CRA.

General

• Cytology may be distinctive.

Cytology

Features:

• Cannonballs (non-specific).
• Suggestive of CRA:
  • Pseudostratified cells.
  • Columnar cells.

Note:

• See adenocarcinoma section above for other types of adenocarcinoma.

Serous carcinoma

Main article: Serous carcinoma

General

• S. Boerner believes one can and ought to separate adenocarcinoma from serous carcinoma.

Microscopic

Features:

• Large nucleoli.
• Cilia.
• Abnormal architecture:
  • Large clusters of cells / micropapillae (?).
  • Nuclear overlap.
  • +/-True papillae.

Note 1 - classic features of serous (see gynecologic pathology article):

• Columnar cells.
• Cilia.
• Papillae.
• Psammoma bodies.

DDx of serous carcinoma (found in ascites fluid):

• Cervix.
• Endometrium.
  • Intravacuolar neutrophils are erroneously believed to be indicative of this.
• Uterine tube.
• Ovary.
• Primary peritoneal.

Images

www:

• Ascites fluid serous adenocarcinoma (nagoya-u.ac.jp).

• 

  Serous carcinoma - cytology - low mag. (WC)

• 

  Serous carcinoma - histology - high mag. (WC)

IHC

• WT-1 +ve.
• CA-125 +ve.
• D2-40 +ve.

Lymphoma

General

• Can only be reasonably certain for large cell lymphomas, e.g. DLBCL.
  • The diagnosis of small cell lymphomas relies on architecture and immunostains.

Cytology

Features:

• Dyscohesive cells ~2x a resting lymphocyte - usually with scant blue cytoplasm.

DDx:

• Small cell carcinoma.
• Other small round cell tumours.

Images

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  Lymphoma - intermed. mag.

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  Lymphoma - high mag.

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  Lymphoma - very high mag.

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  Lymphoma - high mag.

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  Lymphoma - very high mag.

See also

• Cytopathology.
• Urine cytopathology.
• Pulmonary cytopathology.
• Basics.
• Urothelium.

External links

• Mesothelioma (histopathology-india.net).
• Respiratory cytopathology (Australian Society).