Pathology of mesothelioma
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The incidence of mesothelioma has been gradually increasing in Japan, and the underlying factor for this is considered to be the increase in the amount of asbestos imported into Japan between 1960 and 1975. Mesothelioma can be roughly divided into localized and diffuse types, but the former is extremely rare. In making a diagnosis of mesothelioma, it is important to confirm the location of tumor and the specific gross findings before histological examination. Mesothelioma can be categorized histologically as epithelioid type, sarcomatoid type, biphasic type, desmoplastic type, among others. It can take many forms; consequently, there are many diseases to be differentiated when the diagnosis of mesothelioma is based on histological analyses. Immunohistochemical stains are useful for making a diagnosis, but the correct combination of antibodies as positive or negative markers should be selected and a comprehensive assessment of the staining results is necessary. The accuracy of the pathological diagnosis is very important to the patients because they can be receive official compensation or relief when the diagnosis of mesothelioma is confirmed. Under present conditions, both clinicians and pathologists must make a concerted effort to improve the accuracy of the diagnosis of mesothelioma.
KeywordsAntibody Diagnostic accuracy Differential diagnosis Immunohistochemistry Mesothelioma
Incidence of mesothelioma
Mesothelioma is a malignant tumor that originates in the pleura, peritoneum, pericardium and tunica vaginalis, all locations where a lining of normal mesothelial cell is present. According to the official data of Ministry of Health, Labor and Welfare in Japan, the number of death due to mesothelioma was 500 in 1995, increasing gradually to 953 in 2004. This increase appears to parallel the increase of the amount of asbestos imported into Japan between 1960 and 1975, given that the latent period from the beginning of exposure to asbestos and an initial diagnosis of mesothelioma is approximately 40 years.
More detailed examination of the 878 patients who officially died from mesothelioma in 2003 reveals that the male:female ratio was almost 3:1 and that the peak of age of patients was 60+ in males and 70+ in females. The location of the mesothelioma was in the pleura in 84% of the cases, in the peritoneum in 12% and in the pericardium in 1%; there were not cases of mesothelioma in the tunica vaginalis. A larger proportion of females had mesothelioma in the peritoneum and pericardium than in the pleura .
General findings on mesothelioma
Mesothelioma can be roughly classified into localized and diffuse types, with the incidence of the latter being much higher than that of the former . The localized form of mesothelioma was more frequently diagnosed in the past; however, most of the localized forms are currently diagnosed as a solitary fibrous tumor , which is a separate entity from mesothelioma based on immunohistochemical phenotyping (positive for CD34, a marker of primitive endothelial cell) and has no relation to asbestos exposure .
At the early stage of pleural mesothelioma, small nodules are found in the parietal pleura (not in the visceral pleura) that eventually extend along the pleural surface. Eventually, parietal and visceral pleurae show adhesion, and the tumor encloses the entire lung parenchyma. Very few cases of peritoneal mesothelioma have been reported at the early stage and, consequently, little is known in terms of pathology and disease progression during the early stage . Most of peritoneal mesothelioma is found as a diffusely extensive tumor involving intestinal serosa or a large tumor located at the omentum or mesentery.
Following the initial diagnosis of mesothelioma, it is important to confirm the location of the tumor and its gross findings before histological examination. In the case of a pleural mesothelioma, a tumor in the lung parenchyma suggests lung cancer with a pleural extension. In females with peritoneal extension, the ovary should be carefully examined as the primary site of the tumor because the differential diagnosis between ovarian cancer and peritoneal mesothelioma is difficult and can only be made on the basis of histological analyses.
Histology of mesothelioma
Histological classification of mesothelioma 
1. Epithelioid mesothelioma
2. Sarcomatoid mesothelioma
(1) Desmoplastic mesothelioma
3. Biphasic mesothelioma
(1) Lymphohistiocytoid mesothelioma
(2) Deciduoid mesothelioma
(3) Anaplastic mesothelioma
(4) Well differentiated papillary mesothelioma
Differential diagnosis of mesothelioma
Usefulness of immunohistochemistry in an accurate diagnosis
Antibodies used in the immunohistochemical staining for differential diagnosis
Type of mesothelioma
Myo D1, Myoglobin
In the case of epithelioid mesothelioma, calretinin, WT1, thrombomodulin, mesothelin and D2-40 can be applied as a mesothelial cell marker [18, 19, 20, 21, 22]. CEA, TTF-1, Napsin A and surfactant apoprotein are used as markers for lung adenocarcinoma. In the case of ovarian serous papillary adenocarcinoma, we recommend CEA, Ber-EP4, MOC-31 and ER (estrogen receptor) as positive markers .
The antibodies chosen for sarcomatoid mesothelioma are very different from those used for epithelioid mesothelioma. In the case of sarcomatoid mesothelioma, cytokeratin (AE1/AE3 or CAM5.2 as antibodies) exhibits a high specificity and is the most useful . On the other hand, because the diagnosis for true sarcoma is based on the specific differentiation of tumor cells, mesothelioma is eliminated by making its differentiation clear. For example, the following antibodies are known to be useful: MyoD1, desmin and myoglobin for rhabdomyosarcoma; desmin, α-SMA and h-caldesmon for leiomyosarcoma; S-100p for malignant nerve sheath tumor; KP-1 for malignant fibrous histiocytoma .
The most difficult tumor to be differentiated from sarcomatoid mesothelioma of pleura is sarcomatoid carcinoma (spindle cell carcinoma, pleomorphic carcinoma) of the lung. When immunohistochemical stainings are used, both respond positively to cytokeratin . In this case, therefore, the gross finding or the clinical diagnosis by imaging is very important, as already mentioned.
Immunohistochemical stains may be useful in differentiating between fibrous pleuritis and desmoplastic mesothelioma. Desmin is positive for spindle cells of the fibrous pleuritis, while desmin is negative for tumor cells of the sarcomatoid mesothelioma . The combination of EMA, desmin and p53 is useful for differentiating between reactive mesothelial hyperplasia and early-stage epithelioid mesothelioma. Reactive mesothelial cells are positive for desmin and negative for EMA and p53 .
Compensation or relief of patients
In the compensation system for occupational exposures to asbestos and in the new law for non-occupational exposure to asbestos, if the diagnosis of mesothelioma is certain, it can almost always be presumed to be related to asbestos exposure and the patients can receive compensation or relief. Therefore, the accuracy of the pathological diagnosis as mesothelioma is very important. However, a rough estimate is that approximately 10–15% of mesothelioma patients receive an inadequate diagnosis. In the committee for the judgement of patients’ relief, 30% of applicants are judged as not having mesothelioma or the decision is deferred until additional evidence is provided. It is therefore essential that Japanese clinicians and pathologists make an effort to improve the accuracy of the diagnosis as mesothelioma. In particular, the pathologists must improve the accuracy of the pathological diagnosis using adequate immunohistochemical stains.
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