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Mesothelial cytopathology - Libre Pathology

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.

• Sensitivity moderate for malignancy (60%).^[1]

• 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.

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.

Strongly suggestive of malignancy:

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

May be suggestive:

• High NC ratio.

• 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.

• Hepatocellular carcinoma (HCC) may be associated with ascites... but it is rarely positive for malignant cells.^[2]
  • HCC in ascites fluid is super rare -- I haven't seen a case.^[3]

Often seen in the context of:

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

Features:^[4]

• "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.

• Peritoneal wash - benign mesothelial cells in sheets (WC)

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

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

• May be due to any number of causes.
• Can be severe in the context of (peritoneal) dialysis.^[5]

See mesothelioma.

• PF - high mag. (WC)

• PF - very high mag. (WC)

• PF - very high mag. (WC)

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. 

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.

Features:

• Eosinophils >10%.

• History of rheumatoid arthritis.
• Cytologic appearance considered to be pathognomonic.^[6]

Features:^[6]

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

Note:

• Necrotizing granulomatous inflammation.

• AKA systemic lupus erythematosus pleuritis.

• Not common.
• Distinctive cytology.

Features:

• Lupus erythematosus cells, usually abbreviated LE cells:^[7]
  • Pink blobs (representing a denatured nuclei) - phagocytosed by a neutrophil.^[8]

Image:

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

• 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.

Features:^[9]

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:^[9]

Note 1:

• Best assessed on single cells.

www:

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

• Mesothelioma - 1 (WC)

• Mesothelioma - 2 (WC)

• Calretinin +ve.
• WT-1 +ve.
• D2-40 +ve.
• TTF-1 -ve.
• CEA -ve.
• p63 -ve.^[10]

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

Adenocarcinoma in fluid - features:^[11]

• 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:^[11]

• Breast.
• Ovary.
• Lung.
• GI.

• Adenocarcinoma - high mag. (WC)

• Adenocarcinoma - very high mag. (WC)

• Lung adenocarcinoma - high mag. (WC)

• Lung adenocarcinoma - very high mag. (WC)

• Lung adenocarcinoma - high mag. (WC)

• Lung adenocarcinoma - very high mag. (WC)

• Adenocarcinoma - high mag. (WC)

• Adenocarcinoma - very high mag. (WC)

• Adenocarcinoma - very high mag. (WC)

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

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

Breast:

• ER +ve/-ve.
• Calretinin -ve.

Colon:

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

Lung:

• TTF-1 +ve.
• Calretinin -ve.

• May be abbreviated CRA.

• Cytology may be distinctive.

Features:

• Cannonballs (non-specific).
• Suggestive of CRA:^[11]
  • Pseudostratified cells.
  • Columnar cells.

Note:

• See adenocarcinoma section above for other types of adenocarcinoma.

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

Features:

• Large nucleoli.^[12]
• Cilia.^[13]
• Abnormal architecture:^[14]
  • Large clusters of cells / micropapillae (?).
  • Nuclear overlap.
  • +/-True papillae.^[15]

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.^[15]
• Uterine tube.
• Ovary.
• Primary peritoneal.

www:

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

• Serous carcinoma - cytology - low mag. (WC)

• Serous carcinoma - histology - high mag. (WC)

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

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

Features:

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

DDx:

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

• Lymphoma - intermed. mag.

• Lymphoma - high mag.

• Lymphoma - very high mag.

• Lymphoma - high mag.

• Lymphoma - very high mag.

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

1. ↑ Karoo, RO.; Lloyd, TD.; Garcea, G.; Redway, HD.; Robertson, GS. (May 2003). "How valuable is ascitic cytology in the detection and management of malignancy?". Postgrad Med J 79 (931): 292-4. PMID 12782778.
2. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 679. ISBN 978-1416025887.
3. ↑ SB. 8 January 2010.
4. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 674. ISBN 978-1416025887.
5. ↑ Selvaggi, SM.; Migdal, S. (1990). "Cytologic features of atypical mesothelial cells in peritoneal dialysis fluid.". Diagn Cytopathol 6 (1): 22-6. PMID 2323293.
6. ↑ ^{6.0 6.1} Naylor, B.. "The pathognomonic cytologic picture of rheumatoid pleuritis. The 1989 Maurice Goldblatt Cytology award lecture.". Acta Cytol 34 (4): 465-73. PMID 2197838.
7. ↑ URL:http://www.tabers.com/tabersonline/ub/view/Tabers/143167/34/L_E__cell. Accessed on: 12 April 2012.
8. ↑ URL: http://library.med.utah.edu/WebPath/IMMHTML/IMM008.html. Accessed on: 12 April 2012.
9. ↑ ^{9.0 9.1} Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 359-60. ISBN 978-0470519035.
10. ↑ Pu, RT.; Pang, Y.; Michael, CW. (Jan 2008). "Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions.". Diagn Cytopathol 36 (1): 20-5. doi:10.1002/dc.20747. PMID 18064689.
11. ↑ ^{11.0 11.1 11.2} Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 675. ISBN 978-1416025887.
12. ↑ Kuebler, DL.; Nikrui, N.; Bell, DA.. "Cytologic features of endometrial papillary serous carcinoma.". Acta Cytol 33 (1): 120-6. PMID 2916358.
13. ↑ http://www3.interscience.wiley.com/journal/112702002/abstract?CRETRY=1&SRETRY=0
14. ↑ Weir, MM.; Bell, DA. (Oct 2001). "Cytologic identification of serous neoplasms in peritoneal fluids.". Cancer 93 (5): 309-18. PMID 11668465.
15. ↑ ^{15.0 15.1} Boerner, S. 12 January 2010.

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

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