Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis: A Systematic Review Compared With a Standardized Panel of Antibodies-A New Proposal That May Influence Pathologic Practice

Our plain-English summary of Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis: A Systematic Review Compared With a Standardized Panel of Antibodies-A New Proposal That May Influence Pathologic Practice, by N. Le Stang, L. Burke, G. Blaizot, et al (Archives of Pathology & Laboratory Medicine, 2020).

The study

• Authors: N. Le Stang, L. Burke, G. Blaizot, A.R. Gibbs, P. Lebailly, B. Clin, N. Girard, F. Galateau-Sallé, MESOPATH and EURACAN networks
• Journal: Archives of Pathology & Laboratory Medicine
• Published: 2020;144(4):446-456
• Type of article: Systematic review
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Context.—: Pleural mesothelioma is a rare cancer with an often-challenging diagnosis because of its potential to be a great mimicker of many other tumors. Among them, primary lung and breast cancers are the 2 main causes of pleural metastasis. The development and application of targeted therapeutic agents have made it even more important to achieve an accurate diagnosis. In this setting, international guidelines have recommended the use of 2 positive and 2 negative immunohistochemical biomarkers.

Objectives.—: To define the most highly specific and sensitive minimum set of antibodies for routine practice to use for the separation of epithelioid malignant mesothelioma from lung and breast metastasis and to determine the most relevant expression cutoff.

Design.—: To provide information at different levels of expression of 16 mesothelial and epithelial biomarkers, we performed a systematic review of articles published between 1979 and 2017, and we compared those data to results from the Mesothelioma Telepathology Network (MESOPATH) of the standardized panel used in routine practice database since 1998.

Results.—: Our results indicate that the following panel of markers-calretinin (poly)/thyroid transcription factor 1 (TTF-1; clone 8G7G3/1) and calretinin (poly)/estrogen receptor-α (ER-α; clone EP1)-should be recommended; ultimately, based on the MESOPATH database, we highlight their relevance which are the most sensitive and specific panel useful to the differential diagnosis at 10% cutoff.

Conclusions.—: Highlighted by their relevance in the large cohort reported, we recommend 2 useful panels to the differential diagnosis at 10% cutoff.

In plain English

This article combined a systematic review with French national case data. It asked which laboratory stains (immunohistochemical markers) best separate epithelioid malignant pleural mesothelioma from lung and breast adenocarcinoma spread to the pleura. The review used 88 articles from 1979 to 2017, covering 2933 malignant mesotheliomas, 3123 lung adenocarcinomas and 383 breast adenocarcinomas. It calculated sensitivity and specificity at cutoffs from 1% to 75% of stained tumor cells. These results were compared with biopsies certified by France's MESOPATH network from 1998 to 2017: 6571 epithelioid mesotheliomas, 149 lung and 41 breast adenocarcinomas. In the review, calretinin was the most sensitive and specific mesothelioma marker. In MESOPATH data at a 10% cutoff, positive calretinin with negative TTF-1 showed 98% sensitivity (95% CI 97 to 98) in 5290 mesotheliomas and 82% specificity (74 to 88) in 140 lung adenocarcinomas. Positive calretinin with negative estrogen receptor alpha showed 98% sensitivity (97 to 99) in 1152 mesotheliomas and 71% specificity (52 to 86) in only 31 breast adenocarcinomas. The authors recommended these two pairs at a 10% cutoff. They noted publication bias and differences in laboratory methods across studies. Asbestos exposure was not studied.

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: Systematic review of 88 published articles (1979 to 2017), compared with cases from the French national mesothelioma pathology network (MESOPATH) certified 1998 to 2017
• Who was studied: Literature: 2933 malignant mesotheliomas with an epithelioid component, 3123 lung adenocarcinomas and 383 breast adenocarcinomas. MESOPATH (France, 1998 to 2017): 6571 epithelioid malignant mesotheliomas and 602 pleural metastases from carcinomas, described as 149 lung adenocarcinomas and 41 breast adenocarcinomas, all on formalin-fixed, paraffin-embedded biopsy tissue.
• Exposure: Not an asbestos exposure study. What was evaluated was immunohistochemical markers. Mesothelial markers: calretinin, D2-40, EMA, keratin 5/6, keratin AE1/AE3, mesothelin, thrombomodulin, WT1, plus BAP1, p16 and p53 in MESOPATH. Carcinoma markers: CEA, BER-EP4, B72.3, CD15, MOC-31, TTF-1, BG-8, estrogen receptor alpha. Positivity was assessed at several cutoffs of stained tumor cells.
• Main results:
  • The literature pool comprised 2933 malignant mesotheliomas (2540 epithelioid, 276 biphasic, 115 not specified), 3123 lung adenocarcinomas and 383 breast adenocarcinomas.
  • In the literature review, calretinin was the most sensitive and specific mesothelial marker. At a 1% cutoff, sensitivity was 97% (95% CI 95 to 98) in 568 mesotheliomas and specificity was 87% (84 to 90) in 698 lung and breast adenocarcinomas. At a 10% cutoff, sensitivity was 88% (82 to 93) and specificity 94% (91 to 96).
  • In the literature review, TTF-1 showed 100% specificity at all cutoffs studied for separating mesothelioma from lung adenocarcinoma. It was more sensitive at the 1% and 10% cutoffs.
  • In MESOPATH data, calretinin above 10% of cells had a sensitivity of 95% (95% CI 94 to 96) in 6183 epithelioid mesotheliomas. Its specificity was 92% (86 to 96) in 146 lung adenocarcinomas and 79% (62 to 91) in 34 breast adenocarcinomas.
  • In MESOPATH data at a 10% cutoff, the calretinin-positive plus TTF-1 pair had a sensitivity of 98% (95% CI 97 to 98) in 5290 epithelioid mesotheliomas. Its specificity was 82% (74 to 88) in 140 lung adenocarcinomas.
  • In MESOPATH data at a 10% cutoff, the calretinin-positive plus estrogen receptor alpha pair had a sensitivity of 98% (95% CI 97 to 99) in 1152 epithelioid mesotheliomas. Its specificity was 71% (52 to 86) in 31 breast adenocarcinomas.
  • The authors described these pairs as a minimal panel of one positive and one negative marker.
  • For separating mesothelioma from breast adenocarcinoma, estrogen receptor alpha had the highest values. In MESOPATH data, sensitivity was 81% (95% CI 63 to 93) in 41 breast adenocarcinomas and specificity was 100% (99 to 100) in 1412 epithelioid mesotheliomas.
  • Loss of BAP1 staining was highly specific against lung and breast adenocarcinomas. However, its sensitivity was 65% (95% CI 62 to 67) in 1591 MESOPATH epithelioid mesotheliomas.
• The authors' conclusion: The authors recommended a standardized panel at a 10% cutoff: calretinin (polyclonal) with TTF-1 (clone 8G7G3/1) for lung adenocarcinoma metastasis, and calretinin (polyclonal) with estrogen receptor alpha (clone EP1) for breast adenocarcinoma metastasis. They said this would optimize cost while respecting the accuracy of the antibodies. They concluded that their review validates the International Mesothelioma Panel recommendations.
• Limitations the authors state:
  • The authors acknowledged publication bias linked to the ongoing search for new antibodies.
  • Data quality varied across studies: number of subjects, analytic methods and quality assurance, choice of antibody clones, laboratory procedures and how staining patterns were evaluated.
  • The sensitivity of monoclonal CEA in MESOPATH data was poor (30%), which the authors attributed to lung adenocarcinoma metastases mainly being sent when monoclonal CEA was negative.
  • The results for BG-8 and B72.3 against breast adenocarcinoma need confirmation in larger series.
  • There were few breast metastases, including for the WT1 plus estrogen receptor alpha pair.

Topics

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

Medical terms in this study, explained in our Lexicon: Differential Diagnosis, Epithelioid, Malignant Mesothelioma, Metastasis, Systematic Review, Pleural Mesothelioma, Biomarker, Mesothelioma.

Related studies

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• Evaluation of androgen receptor and GATA binding protein 3 as immunohistochemical markers in the diagnosis of metastatic breast carcinoma to the lung — Y. Hattori, A. Yoshida, et al. (2015)
• Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia — K. Kushitani, V.J. Amatya, et al. (2016)
• Metastases to the breast: differential diagnosis from primary breast carcinoma — B. Vergier, M. Trojani, et al. (1991)
• Validation of a minimal panel of antibodies for the diagnosis of malignant pleural mesothelioma — S.C. Kao, K. Griggs, et al. (2011)
• Utility of a CEA, CD15, calretinin, and CK5/6 panel for distinguishing between mesotheliomas and pulmonary adenocarcinomas in clinical practice — T. Mohammad, J. Garratt, et al. (2012)

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