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invasive mesothelioma

Thursday 22 December 2005

MM; malignant mesothelioma; diffuse malignant mesothelioma

Digital cases

- JRC:1606 : Pseudomesotheliomatous carcinoma ? Epithelial mesothelioma ?
- JRC:1604 : Pleural sarcomatoid mesothelioma with osteocartilagenous differentiation.
- JRC:9814 : Pleural epithelioid mesothelioma.
- JRC:9815 : Pleural fibrous mesothelioma.
- JRC:9814 : Pleural epithelioid mesothelioma.
- JRC:9816 : Pleural epithelioid mesothelioma.
- JRC:9835 : Pleural fibrous mesothelioma.

Localization

- pleural mesothelioma
- pericardial mesothelioma
- peritoneal mesothelioma

Types

- epithelial mesothelioma
- mixed and fibrous mesothelioma
- sarcomatous mesothelioma

Cytology

Cytological diagnosis of Mesothelioma is difficult. A persistent effusion with atypical mesothelial cells is suggestive of mesothelioma since reactive effusions are usually self-limiting.

Of the three main histological types of mesothelioma (Epithelial ; Mixed and Fibrous or Sarcomatous), the epithelial variety is the most frequent source of effusions and therefore the type most often seen cytologically. The sarcomatous variant is the least frequent type to produce an effusion.

Fluid frequently bloodstained and may be a copious effusion, sometimes small. Supernatant fluid can be very viscous, like synovial fluid, due to hyaluronic acid content.

Cytology-only diagnosis on effusion fluids remains controversial, and cytology in this setting cannot assess invasion, but it can suggest a diagnosis of pleural epithelioid malignant mesothelioma (MM) at varying levels of confidence.

Pointers to a diagnosis of malignant mesothelioma (MM) include the profusion of the mesothelial proliferation, morular-papillary structures comprising 50 cells or more (especially in the pleura), cytological atypia, macronucleoli, frequent cytoplasmic vacuoles, and a single population of atypical cells to aid in the exclusion of secondary carcinoma.

However, some cases of confirmed benign reactive mesothelial proliferations (BMP) can display considerable cytological atypia, whereas confirmed invasive epithelioid malignant mesothelioma (MM) can be deceptively bland in appearance, with cytological overlap between the two.

Other findings such as scalloped borders of cell clusters, intercellular fenestrations, variation in cytoplasmic staining and its ‘density’, and low nuclear-to-cytoplasmic ratios can be found in both epithelioid MM and reactive mesothelial hyperplasias.

These remarks concern only MM with a significant epithelial component: diagnosis of sarcomatoid and especially desmoplastic MM is rarely achievable by cytology except for fine-needle aspiration biopsy (FNAB), and even those cases require close correlation with clinical and imaging data, in the present authors’ experience.

Although a cytology-only diagnosis of MM based on effusion fluid can be made at a high order of specificity in some cases, the main problem is one of low sensitivity, reported to be in the range of about 30–75%, and as low as 16% for a ‘positive’ diagnosis after the exclusion of ‘suspicious’ findings.

In a study of 162 cases of MM, effusion fluid cytology showed high specificity (∼99%) when all criteria for diagnosis were fulfilled. Those criteria comprised:
- (1) cells with mesothelial features as caricatures of reactive mesothelial cells;
- (2) binucleated and multinucleated cells;
- (3) minute pink granules in the background in Giemsa-stained smears;
- (4) a single population showing a transition between benign-appearing cells and cytologically malignant cells;
- (5) large round nuclei with abundant cytoplasm;
- (6) tinctorial gradation of staining within the cytoplasm and evidence of microvilli at the cell periphery;
- (7) vacuolated cells, described by Welker et al as ‘foamy’;
- (8) large and numerous clusters of mesothelial cells.

However, the sensitivity was only 47.5% when not all criteria were fulfilled. The sensitivity improved to 71– 91% by interpreting the cytological findings together with effusion fluid hyaluronic acid concentrations.

Very rarely, intracytoplasmic rod-like or cylindrical crystalloids may be found and may impart a Gaucher-like appearance of the tumour cells in histological sections; by electron microscopy, such crystalloids represent complex scroll-like granular crystalloids within the endoplasmic reticulum, presumably representing polymerised glycosaminoglycan material such as hyaluronic acid, and so far as we are aware they have been reported only in epithelioid MM.

Cytology: low power diagnosis

- 1. A highly cellular deposit, unless too heavily blood stained.
- 2. Mesothelial cells predominate, arranged singly, paired and in clusters giving an exaggerated picture of reactive change.
- 3. Large cell balls may be present, sometimes with a connective tissue core (papillary structures).
- 4. Finely granular pink staining backround (hyaluronic acid) in viscous fluids (a minority of cases).

Cytology: high power diagnosis

- 1. A spectrum from normal looking mesothelial cells to abnormally large forms, instead of two distinct cell populations as seen in metastatic carcinoma.
- 2. Bi- and multinucleated cells seen, with nuclear pleomorphism.
- 3. Nuclei enlarged but also voluminous ; nucleocytoplasmic ratio remains relatively low.
- 4. Mitoses may be present, but but these also occur in reactive effusions.
- 5. Cytoplasmic features: densely stained cytoplasm but may show foamy or fatty vacuolation or larger vacuoles containing hyaluronic acid.
- 6. Biphasic cytoplasmic staining in Papanicolaou preparations: central pink staining, periphery green.
- 7. Close cell to cell apposition with a narrow window between the two cells (a characteristic mesothelial cell arrangement).
- 8. Cell in cell engulfment is frequently seen.
- 9. Fringes of microvilli and pseudopodia (cytoplasmic knobs) often present.
- 10. Pyknotic shrunken cells develop a "squamous" look in Pap preparation.
- 11. Nuclear chromatin not well seen with Giemsa stain, may be irregular in Pap preparations.
- 12. Occasionally psammoma bodies are present.

Cytology: Summary of Effusion Cytology in Mesothelioma

- 1. The correct diagnosis is usually possible given an adequate cytological sample.
- 2. The easiest samples are those with many epithelial-type aggregates and many single malignant cells.
- 3. Cell aggregates are the most helpful feature in diagnosing the mesothelial nature of the malignancy.
- 4. Single cells or small clusters are the most helpful feature in diagnosing the mesothelial nature of malignancy.
- 5. A panel of special stains and immunocytochemical markers is necessary to distinguish mesothelioma from adenocarcinoma.

Differential Diagnosis of Mesothelioma in Effusions

Mesothelioma must be differentiated from metastatic carcinoma at one extreme and from a benign reactive effusion at the other end of spectrum.

Both of these may prove extremely difficult and suspicious reports are therefore more frequent than eith other tumours, but it is important to recrd suspicious diagnoses to add weight to an industrial compensation claim.

Repeated examination of fluid may be necessary and recurring abnormal picture adds weight to a diagnosis of mesothelioma rather than a reactive effusion.

Immunochemistry

- EMA

  • A strong circumferential immunolabelling of mesothelial cells for epithe- lial membrane antigen (EMA) is evidence in favour of MM as opposed to BMP (E29 clone).

- other indicators of MM

  • glucose transporter-1 (GLUT-1)
  • insulin-like growth factor messenger RNA-binding protein 3 (IMP3)
  • X-linked inhibitor of apoptosis
  • p53
  • bcl-2

- immunolabelling for desmin is claimed to be evidence in favour of a BMP.

- D2-40+ (15389250)

- Tenascin XB

  • Tenascin XB (TNXB) has been identified as a gene that is more highly expressed in malignant mesothelioma compared with ovarian/peritoneal serous carcinoma based on gene expression array analysis. Tenascin-X may be a new diagnostic marker of malignant mesothelioma in the differential diagnosis of cancers involving the serosal cavities, particularly in the differential diagnosis between this tumor and ovarian/peritoneal serous carcinoma. (19738457)

FISH

- fluorescence in-situ hybridisation (FISH) for deletion of p16/CDKN2A

  • homozygous deletion of p16/ CDKN2A, as demonstrated by FISH, may be useful for the distinction between MM and BMP, with sensitivity and specificity in one study that were superior to immunolabelling for GLUT.
  • Studies have reported such deletions of p16/CDKN2A in 43–70% of pleural MM (mainly but not exclusively epithelioid MM), but not in reactive mesothelial hyperplasias.
  • The p16 deletion was less frequent in peritoneal mesotheliomas than in pleural MM.

Links

- Cytology: http://www.histopathology-india.net/MesoCyto.htm

References

- Tenascin-X is a novel diagnostic marker of malignant mesothelioma. Yuan Y, Nymoen DA, Stavnes HT, Rosnes AK, Bjørang O, Wu C, Nesland JM, Davidson B. Am J Surg Pathol. 2009 Nov;33(11):1673-82. PMID: 19738457

- Carbone M, Emri S, Dogan AU, Steele I, Tuncer M, Pass HI, Baris YI. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nat Rev Cancer. 2007 Feb;7(2):147-54. PMID: 17251920

- Musti M, Kettunen E, Dragonieri S, Lindholm P, Cavone D, Serio G, Knuutila S. Cytogenetic and molecular genetic changes in malignant mesothelioma. Cancer Genet Cytogenet. 2006 Oct 1;170(1):9-15. PMID: 16965949

- Robinson BW, Lake RA. Advances in malignant mesothelioma.
N Engl J Med. 2005 Oct 13;353(15):1591-603. PMID: 16221782

- Chu AY, Litzky LA, Pasha TL, Acs G, Zhang PJ. Utility of D2-40, a novel mesothelial marker, in the diagnosis of malignant mesothelioma. Mod Pathol. 2005 Jan;18(1):105-10. PMID: 15389250

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