Skip to main content
Log in

Cytological diagnosis of malignant mesothelioma—improvement by additional analysis of hyaluronic acid in pleural effusions

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript


Cytology allows the diagnosis of malignant mesothelioma (MM) from effusions with high specificity but low sensitivity. Conversely, elevated levels of hyaluronic acid (HA) in effusions are sensitive indicators of MM, although specificity is insufficient. We studied whether the cytological diagnosis of MM could be improved by HA analysis. HA was analysed in patients with histologically confirmed MM (n = 162), adenocarcinoma or other malignant tumours (n = 100) and in 90 patients with benign pleural diseases. In 77 out of 162 effusions, all, and in 33 some, cytological criteria of MM were satisfied. The cut-off value of HA showing maximum diagnostic reliability (86%) regarding MM was 30 mg/l (sensitivity 87%, specificity 86%). A HA value of 100 mg/l yielded 39 and 98%, respectively. Seventy three out of 77 patients with cytological findings indicative of MM showed HA levels greater than 30 mg/l as well as 27 of 33 patients with suspicious lesions. These 100 patients were correctly recognised as having MM. The addition of HA analysis to cytology, requiring all or some criteria of MM as positive, increased sensitivity for MM from 48 to 71–91%, whereas specificity only slightly decreased to 94–96%. We conclude that the combined cytological and HA analysis of pleural effusions had the potential to improve the diagnosis of MM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others


  1. Achatzy R, Beba W, Ritschler R, Worn H, Wahlers B, Macha HN, Morgan JA (1989) The diagnosis, therapy and prognosis of diffuse malignant mesothelioma. Eur J Cardiothorac Surg 3:445–447

    Article  PubMed  CAS  Google Scholar 

  2. Antman K, Shemin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Corson J (1988) Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana–Farber Cancer Institute and Brigham and Women’s Hospital experience over two decades, 1965–1985. J Clin Oncol 6:147–153

    PubMed  CAS  Google Scholar 

  3. Antony VB (2003) Immunological mechanisms in pleural disease. Eur Respir J 21:539–544

    Article  PubMed  CAS  Google Scholar 

  4. Atagi S, Ogawara M, Kawahara M, Sakatani M, Furuse K, Ueda E, Yamamoto S (1997) Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural effusions: likelihood ratios for malignant mesothelioma. Jpn J Clin Oncol 27:293–297

    Article  PubMed  CAS  Google Scholar 

  5. Dahl IM, Solheim OP, Erikstein B, Müller E (1989) A longitudinal study of the hyaluronan level in the serum of patients with malignant mesothelioma under treatment. Hyaluronan as an indicator of progressive disease. Cancer 64:68–73

    Article  PubMed  CAS  Google Scholar 

  6. Friman C, Hellström PE, Juvani M, Riska H (1977) Acid glycosaminoglycans (mucopolysaccharides) in the differential diagnosis of pleural effusion. Clin Chim Acta 76:357–361

    Article  PubMed  CAS  Google Scholar 

  7. Fuhrman C, Duche JC, Chouaid C, Abd Alsamad I, Atassi K, Monnet I, Tillement JP, Housset B (2000) Use of tumor markers for differential diagnosis of mesothelioma and secondary pleural malignancies. Clin Biochem 33:405–410

    Article  PubMed  CAS  Google Scholar 

  8. Hillerdal G, Lindqvist U, Engström-Laurent A (1991) Hyaluronan in pleural effusions and in serum. Cancer 67:2410–2414

    Article  PubMed  CAS  Google Scholar 

  9. Martensson G (1990) Diagnosing malignant pleural mesothelioma. Eur Respir J 3:985–986

    PubMed  CAS  Google Scholar 

  10. Martensson G, Thylen A, Lindquist U, Hjerpe A (1994) The sensitivity of hyaluronan analysis of pleural fluid from patients with malignant mesothelioma and a comparison of different methods. Cancer 73:1406–1410

    Article  PubMed  CAS  Google Scholar 

  11. Matzel W (1985) Biochemical and cytological features of diffuse mesotheliomas of the pleura. Arch Geschwulstforsch 55:259–64

    PubMed  CAS  Google Scholar 

  12. Meyer K, Chaffee E (1939) Hyaluronic acid in pleural fluid associated with malignant tumour involving pleura and peritoneum. Pro Soc Exp Biol Med 42:797–800

    CAS  Google Scholar 

  13. Parker C, Neville E (2003) Lung cancer * 8: management of malignant mesothelioma 1. Thorax 58:809–813

    Article  PubMed  CAS  Google Scholar 

  14. Peto J, Decarli A, La Vecchia C, Levi F, Negri E (1999) The European mesothelioma epidemic. Br J Cancer 79:666–672

    Article  PubMed  CAS  Google Scholar 

  15. Pettersson T, Froseth B, Riska H, Klockars M (1988) Concentration of hyaluronic acid in pleural fluid as a diagnostic aid for malignant mesothelioma. Chest 94:1037–1039

    PubMed  CAS  Google Scholar 

  16. Renshaw AA, Dean BR, Antman KH, Sugarbaker DJ, Cibas ES (1997) The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Chest 111:106–109

    PubMed  CAS  Google Scholar 

  17. Spriggs AI, Boddington MM (1994) Atlas of serous fluid cytopathology. A guide to the cells of pleural, pericardial, peritoneal and hydrocele fluid. In: Gresham GA (ed) Current histopathology series, vol 14. Kluwer, Dordrecht (1989)

    Google Scholar 

  18. Stevens MW, Leong AS, Fazzalari NL, Dowling KD, Henderson DW (1992) Cytopathology of malignant mesothelioma: a stepwise logistic regression analysis. Diagn Cytopathol 8:333–341

    Article  PubMed  CAS  Google Scholar 

  19. Thylen A, Hjerpe A, Martensson G (2001) Hyaluronan content in pleural fluid as a prognostic factor in patients with malignant pleural mesothelioma. Cancer 92:1224–1230

    Article  PubMed  CAS  Google Scholar 

  20. Welker L, Jörres RA, Costabel U, Magnussen H (2004) Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur Respir J 24:1000–1006

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest statement

L Welker None declared

M Müller None declared

O Holz None declared

E Vollmer None declared

H Magnussen None declared

RA Jörres None declared

Author information

Authors and Affiliations


Corresponding author

Correspondence to L. Welker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Welker, L., Müller, M., Holz, O. et al. Cytological diagnosis of malignant mesothelioma—improvement by additional analysis of hyaluronic acid in pleural effusions. Virchows Arch 450, 455–461 (2007).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: