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Teaching Case 9Clinical SummaryThe patient is an 83 year old male with a pleural based tumor in the right upper lobe. There is no known history of asbestos exposure. Summary of Histologic ExaminationLobectomy revealed a pleural-based tumor that had a distinctive papillary growth pattern as seen on H&E-stained sections (see images below). The case was referred for immunohistochemical studies to distinguish between the diagnoses of mesothelioma and adenocarcinoma. H&E Images
The differential diagnosis of mesothelioma versus adenocarcinoma is one that usually has both medical and legal implications. In order to render a diagnosis that can be defended in a deposition or more formal legal proceedings, clinical history, H&E histology, and ancillary studies, such as immunohistochemistry, must all be taken into consideration. While there have been some excellent recent reviews of the immunohistochemical approaches to this problem [1-4] , many of these studies are out of date, as powerful new positive markers of mesothelioma now exist, and many were not included even in these recent reviews. The question most commonly asked in this clinical setting is: which markers are best used to distinguish mesothelioma from adenocarcinoma (primary to the lung, or metastatic from some other site)? Results of Immunohistochemistry StudiesNegative MarkersTaking an historical perspective, the first markers available to help in the adenocarcinoma v. mesothelioma distinction were "negative markers", that is, proteins expressed in adenocarcinomas but not in mesotheliomas. While there were intrinsic shortcomings to this approach (i.e., it is inherently difficult to confirm a diagnosis by the absence rather than the presence of a particular marker), it was dictated by the markers available at the time. The following chart lists the five most commonly used "negative markers" of mesothelioma. 'Negative' Mesothelial Markers
Of course, the value of a negative marker is in part determined by its sensitivity in adenocarcinomas of different primary sites. For example, markers such as CEA show a very high sensitivity for lung carcinomas (greater than 90%), but their sensitivity for (metastatic) breast cancer is significantly lower, in our experience in the range of 60-70%. In the study we have performed in conjunction with Dr. Hector Battifora, and presented recently at the March 2002 USCAP meeting [13] , we found that the glycoproteins identified by antibody MOC-31 and the Lewis Y antigen identified by antibody Bg8 were clearly the most sensitive markers of carcinoma when primary lung, metastatic breast, and metastatic ovarian carcinomas were considered. The value of a negative marker is also determined by the frequency of "false positives" on mesotheliomas. Most of the literature demonstrates that, when positive on mesotheliomas, markers such as the antibody BerEp4 and MOC31 defined glycoproteins are generally only focally and weakly positive. In our recent study, the specificity of all five "negative markers" was in excess of 90% [13] . The markers which showed the combination of maximal sensitivity and specificity (when considering a range of possible primary sites for carcinoma) in our study were the glycoproteins identified by antibodies BerEp4 and MOC31, as well as the Lewis Y antigen identified by antibody Bg8. Positive MarkersIn recent years a series of positive markers for mesothelioma have been described, and they are listed in the table below: 'Positive' Mesothelial Markers
Calretinin is a calcium-binding protein with both cytoplasmic and nuclear localization; it is expressed widely throughout the central and peripheral nervous systems, but among non-neural tissues shows relatively strong specificity for mesothelial cells and tissues. While the original study by Doglioni and colleagues [14] suggested almost complete specificity for mesothelial cells/mesothelioma among epithelial cells and tumors, more recent studies have confirmed the very high sensitivity of this marker for mesothelioma, but also show expression in a small but significant fraction of adenocarcinomas [15] . Wilms tumor gene product (WT1) is a DNA-binding protein located in the nucleus that plays a critical role in the development of the genitourinary tract. In adult tissues it is expressed in mesangial cells of the kidney, Sertoli cells of the testis, ovarian stromal cells and ovarian surface epithelium, mesothelial cells in the abdomen and thorax, and some smooth muscle and other stromal cells in the GYN tract (e.g., myometrium, endometrial stromal cells). WT-1 is also expressed in mesothelial tumors (epithelioid and sarcomatoid types) [24] as well as tumors derived from the ovarian surface epithelium (a modified mesothelium). More recent studies have confirmed the specificity of this marker for mesothelioma, but several find a low sensitivity than markers such as calretinin [11, 26] . Cytokeratin 5 is found in mesothelium, squamous and transitional epithelium, and myoepithelium. Among carcinomas, expression of cytokeratin 5 is largely restricted to mesotheliomas and squamous cell carcinomas, [16, 17] , although a subset of carcinomas, e.g., of the breast, can also express cytokeratin 5 [27] . Mesothelin was originally known as the CAK1 antigen identified by the antibody K1 [18, 19, 28, 29] . It is a 40 kd cell surface protein that may be involved in cell-cell adhesion, and can now be identified by 'second generation' anti-mesothelin antibodies such as the 5B2 clone. This marker is highly specific for mesothelial cells (and surface ovarian epithelial cells) and, when positive, manifests a linear cell surface immunostaining pattern. While markers such as N-cadherin, thromobomodulin, and HBME-1 have had their advocates, none of these markers have the robustness of the three described above, in our experience. Vimentin is the 'grand-daddy' of positive mesothelioma markers, but a number of carcinomas can co-express vimentin (such as renal cell, endometrial, thyroid, and salivary gland carcinomas), but, more importantly, virtually all carcinomas that display spindle cell features demonstrate co-expression of vimentin.. The following table summarizes the findings of our most recent study [13] ), performed in conjunction with Dr. Hector Battifora, concerning the relative sensitivity of the positive mesothelial markers:
The relative sensitivities of the positive mesothelial markers is altered in the histopathologic setting of spindle cell or sarcomatoid mesothelioma; the sensitivity of markers such as cytokeratin 5 and mesothelin drops significantly, but the sensitivity of markers such as calretinin and WT-1 remains relatively high. The relative specificities of these mesothelial markers also varies (and also is a function of the non-mesothelioma tumors considered in the differential diagnosis, inasmuch as metastatic ovarian carcinomas can co-express many mesothelial markers), with thrombomodulin, cytokeratin 5, mesothelin, and WT-1 showing the highest specificity in our study (in male patients). Turning to the case at hand, immunohistochemical studies revealed the following results using antibodies to mesothelial-restricted marker. Antibodies to calretinin (see figure 4), the Wilms tumor gene product (see figure 5), and cytokeratin 5 (see figure 6) were all negative on this tumor, arguing persuasively against the diagnosis of a mesothelial tumor. Antibodies to calretinin did identify the presence of some non-neoplastic, reactive mesothelial cells, serving as excellent "internal controls" (see figure 4 ).
In contrast, antibodies to markers of adenocarcinomas, e.g., antibodies Bg8 (see Figure 7) and MOC31 (see figure 8) were both uniformly positive on the tumor; note the membranous, uniform pattern of positivity characteristic of these antibodies in adenocarcinomas. In conjunction with the negative mesothelial markers (indeed, even in their absence), the results of these two antibody studies point unequivocally to the diagnosis of adenocarcinoma.
Pleural based adenocarcinomas may represent a form of peripheral primary lung non-small cell carcinoma, but may also represent a metastasis from another primary site. In this case, there was no clinical evidence of a tumor elsewhere; in fact, additional studies employing antibodies to the TTF-1 nuclear transcription factor [30-33] (see figure 9) and the surfactant apoA cytoplasmic marker [34, 35] (see figure 10) together confirm the origin of this tumor in the lung.
Occasionally a peripheral based lung carcinoma can simulate the appearance, clinically, grossly, and even microscopically, of mesothelioma. Indeed, the appellation "pseudomesotheliomatous carcinoma of the lung" has been coined [36, 37] . There is evidence that these mimic pleural mesothelioma not only in their clinical and gross and microscopic appearance, but also in their very poor prognosis [38]. Final DiagnosisPrimary lung nonsmall cell carcinoma References
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