Re-evaluation of histological diagnoses of malignant mesothelioma by immunohistochemistry

Our plain-English summary of Re-evaluation of histological diagnoses of malignant mesothelioma by immunohistochemistry, by H.P. Sandeck, O.D. Røe, K. Kjærheim, et al (Diagnostic Pathology, 2010).

The study

• Authors: H.P. Sandeck, O.D. Røe, K. Kjærheim, H. Willén, E. Larsson
• Journal: Diagnostic Pathology
• Published: 2010;5:47
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: In order to provide reliable tissue material for malignant mesothelioma (MM) studies, we re-evaluated biopsies and autopsy material from 61 patients with a diagnosis of MM from the period of 1980-2002.

Methods: Basic positive (Calretinin, EMA, Podoplanin, Mesothelin) and negative (CEA, Ber-Ep4) immunohistochemical (IHC) marker reactions were determined. If needed, more markers were used. Histological diagnoses were made by three pathologists. Survival data were calculated.

Results: 49 cases (80%) were considered being MM by a high degree of likelihood, five more cases possible MM. Of the remaining seven cases, three were diagnosed as adenocarcinoma, three as pleomorphic lung carcinoma, in one peritoneal case a clear entity diagnosis could not be given. One of the possible MM cases and two of the lung carcinoma cases had this already as primary diagnoses, but were registered as MM.With a sensitivity of 100%, Calretinin and CEA were the most reliable single markers. The amount of MM cells with positive immunoreactivity (IR) for Podoplanin and Mesothelin showed most reliable inverse relation to the degree of atypia.In the confirmed MM cases, there had been applied either no IHC or between one and 18 markers.The cases not confirmed by us had either lacked IHC (n = 1), non-specific markers were used (n = 4), IR was different (n = 1), or specific markers had not shown positive IR in the right part of the tumour cells (n = 3).46 of the 49 confirmed and three of the not confirmed cases had been diagnosed by us as most likely MM before IHC was carried out.

Conclusions: In order to use archival tissue material with an earlier MM diagnosis for studies, histopathological re-evaluation is important. In possible sarcomatous MM cases without any positive IR for positive MM markers, radiology and clinical picture are essential parts of diagnostics. IHC based on a panel of two positive and two negative MM markers has to be adapted to the differential diagnostic needs in each single case. New diagnostic tools and techniques are desirable for cases where IHC and other established methods cannot provide a clear entity diagnosis, and in order to improve MM treatment.

In plain English

This study re-examined archived tissue from Norwegian patients recorded as having malignant mesothelioma between 1980 and 2002, to check diagnoses before research use. Of 73 patients' samples from 19 Norwegian pathology departments, 61 had enough tumour to test. Three pathologists re-diagnosed them with immunohistochemical markers. Of the 61, 49 (80%) were confirmed as mesothelioma. Six were diagnosed on re-evaluation as adenocarcinoma or pleomorphic lung carcinoma. Two of these had already been diagnosed as carcinoma by the original pathologists but were registered as mesothelioma. Six received no definite diagnosis; mesothelioma remained possible in five. Counting only the original pathology reports, the authors found a 15% discrepancy. They suggested it could be explained by missing staining, non-specific markers, differing stain results or inappropriate conclusions. Calretinin and CEA showed 100% sensitivity in confirmed cases. Overall median survival was 12.5 months. Detailed asbestos exposure data were not available. The authors concluded that older archived mesothelioma diagnoses need re-evaluation. They affirmed panels of at least two positive and two negative markers, as far as sensitivity is concerned. They stated their specificity results cannot be generalized.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective re-evaluation (diagnostic review) of archival tissue, using histology and immunohistochemistry, with survival analysis
• Who was studied: Paraffin-embedded tissue (mostly biopsies, a few autopsies) from 73 patients with a diagnosis of malignant mesothelioma, taken 1980 to 2002 and supplied by 19 Norwegian pathology departments. 61 patients (84%) had enough tumour tissue to be evaluated. All patients were donors to the Norwegian Janus serum bank.
• Exposure: Asbestos exposure was not studied directly, and detailed exposure data were not available. An earlier census-based estimate for nearly the same patient group (n = 47) judged occupational asbestos exposure likely in 12 patients, all men, but this could not be validated. No fiber types are reported.
• Main results:
  • Of the 61 evaluable cases, 49 (80%; 40 men, 9 women) were confirmed as malignant mesothelioma: 40 epithelial type, 8 mixed type, and 1 undetermined between epithelial and mixed.
  • In the remaining 12 cases (20%; 10 men, 2 women), the mesothelioma diagnosis was either abolished (n = 7) or put more in doubt (n = 5). On re-evaluation, three were adenocarcinoma and three were pleomorphic lung carcinoma.
  • In one possible-mesothelioma case and two lung carcinoma cases, the original pathology diagnosis already agreed with the re-evaluation, but the cases had been registered as mesothelioma in the Cancer Registry. The authors said this was apparently done by clinicians who did not accept the histological diagnoses.
  • Six cases could not be given a definite diagnosis. Mesothelioma remained one of the possible diagnoses in five of these six.
  • Counting only original histological diagnoses, 9 of 61 (15%) were not confirmed. The authors suggested this could be explained by lack of immunohistochemistry (n = 1), non-specific markers (n = 4), differences in staining results (n = 1), or not appropriate conclusions based on appropriate markers (n = 3).
  • In the 49 confirmed mesothelioma cases, Calretinin was positive in 49/49 and monoclonal CEA was negative in 49/49 (both 100% sensitivity). Sensitivity for the other basic markers was EMA 43/49 (87.8%), Podoplanin 44/46 (95.6%), Mesothelin 44/48 (91.7%) and Ber-Ep4 40/49 (81.6%). In two of the 49 cases, Calretinin was positive in only a few tumour cells.
  • Specificity was judged against only five lung carcinoma reference cases. It was 100% for Calretinin and Mesothelin, and lower for Podoplanin, EMA and monoclonal CEA.
  • In the three confirmed mesothelioma cases with high atypia (grade 3), Podoplanin and Mesothelin staining was low compared with grade 1 to 2 cases.
  • Original diagnostic methods in the confirmed cases: 19 (39%) had been diagnosed without any immunohistochemistry, and at least 26 (53%) with between 1 and 18 markers.
  • Before immunohistochemistry, the authors had judged 46 of the 49 later-confirmed cases (94%) as most likely mesothelioma from standard stained slides alone.
  • Overall median survival was 12.5 months. Peritoneal mesothelioma had the longest median survival, 51.8 months. In multivariate analysis, only peritoneal location, cellular atypia and necrosis contributed significantly.
• The authors' conclusion: The authors concluded that archival tissue with an earlier mesothelioma diagnosis needs histopathological re-evaluation before use in studies, especially diagnoses made before more specific positive markers were introduced. They concluded that the recommendation of at least two positive and two negative markers was affirmed as far as sensitivity is concerned, and that marker choice must be adapted to each case. They considered sarcomatous-type cases with no staining for mesothelial markers insufficient for a definitive pathological diagnosis unless clinical and radiological findings support it. They also said new diagnostic tools are needed.
• Limitations the authors state:
  • The material was not tested against a set of non-mesothelioma tumours, so the specificity results cannot be generalized.
  • Because tissue was scarce, some relevant markers (such as WT-1 and h-Caldesmon) and certain histochemical reactions could not be applied.
  • The material was not representative of the usual distribution of mesothelioma types.
  • There were too few cases for the multivariate survival analysis to be representative.
  • Clinical and radiological information was fragmentary.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunohistochemistry, Autopsy, Calretinin, Podoplanin (D2-40), Mesothelin, Ber-EP4, Adenocarcinoma.

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