Do we need two more mesothelial markers?

The differential diagnosis between epithelial mesothelioma and carcinoma often requires immunohistochemical assays. Currently an antibody panel is used for this purpose because no single antibody has sufficient specificity for either mesothelioma or carcinoma. Thus, the search for new and improved mesothelial markers continues.

In the April issue, Dr. Nelson Ordóñez relates his experience with two markers of lymphatic endothelium, the D2-40–defined antigen and podoplanin that, by happenstance, are also expressed by mesothelial cells [1]. He concludes that these two markers have superior specificity over the current favorites, calretinin and cytokeratins 5/6. Most of Dr. Ordóñez findings are supported by previous publications by other authors [2], [3], [4], [5].

However, while none of the adenocarcinomas studied by Dr. Ordóñez expressed the D2-40–defined antigen or podoplanin, Chu et al. in a previous study reported that a large proportion of serous carcinomas of the ovary expressed D2-40 [3], [4]. Our limited experience to date agrees with the findings of Dr. Ordóñez, that the D2-40–defined antigen is rarely expressed in ovarian carcinomas, but this discrepancy between the published findings of Drs. Ordóñez and Chu et al. remains to be resolved.

But is this a problem? We think not. The vast majority of the diagnostic immunohistochemical markers we currently employ in our daily practice of surgical pathology have relative specificity; this is the reason we use immunodiagnostic panels. Clearly, the diagnostic specificity of the D2-40–defined antigen would be excellent in the case of a pleural tumor in a male, but poor in a peritoneal tumor in a woman. Two other reliable mesothelial markers, mesothelin and WT-1, are almost always expressed by carcinomas of ovarian surface epithelial origin. It is for this reason that we routinely exclude them from the mesothelioma panel in peritoneal tumors in women [6].

Clearly, the composition of any diagnostic panel must be adjusted to the clinical situation to optimize its specificity. For example, if poorly differentiated squamous cell carcinoma (SCC) involving serous membranes enters the differential diagnosis, it is imperative to include p63—a marker present in most SCC—replacing cytokeratins 5/6 that are commonly expressed by both mesothelioma and SCC [7].

Interpreting slides immunostained with the D2-40 monoclonal antibody may be more challenging to the pathologist, however, because of the immunostaining present in lymphatics as well as reactive pneumocytes, as noted in our preliminary studies. Nonetheless, having two additional markers of mesothelial lineage is a welcome development likely to lead to higher diagnostic accuracy in the distinction between epithelial mesothelioma and its mimics.

Another issue is whether D2-40 and antibodies to podoplanin recognize the same or related epitopes since they exhibit remarkable similarities in immunoreactivity. If so, only one of these would be necessary.

Clearly, however, careful and accurate comparative evaluation of these new markers with current ones is needed to decide which ones to incorporate to—and which ones to replace—from our diagnostic panels.