Malignant Mesothelioma

Malignant mesothelioma (MM) is a tumor derived from mesothelial cells, native cells of the body cavities. The pleural cavity is the most common site, with a present ratio of 9:1 with peritoneal tumors. Exposure to asbestos can be documented in about 80% of the cases [[1]]. The disease develops decades after exposure, during which period the neoplastic cells accumulate a variety of chromosomal aberrations [[2]]. The incidence of MM is on the rise in western countries [[1]]. Patients are typically older than 50 years of age, with males being affected slightly more [[2]]. The prognosis is extremely poor, with survival of 4 to 12 months from diagnosis, which has remained largely unaltered by medical intervention [[3]]. New agents, such as the antifolate drug pemetrexed, and currently evaluated as treatment for MM in combination with other drugs [[4]].

The main differential diagnoses of the epithelioid type of MM is metastatic adenocarcinoma (AC) and reactive mesothelial proliferations. Benign mesothelial cells react to a wide variety of stimuli and injuries that break their continuity by proliferation and reactive cellular changes. Consequently, hyperplastic mesothelial cells in various benign clinical settings undergo marked nuclear and cytoplasmic alterations, some of them mimicking the morphology of malignant cells [[5]]. Adenocarcinomas metastatic to serosal surfaces are most commonly of breast, ovary and lung origin. Morphological guidelines for the separation of benign from malignant mesothelium have been described, but are often difficult to implement [[6]]. Consequently, the two most reliable methods for the differentiation between reactive mesothelium, MM and AC are histochemistry/immunohistochemistry and electron microscopy.

Histochemistry/Immunohistochemistry: Histochemical stains that aid in differentiating MM from AC are the PAS, PAS + diastase, alcian blue and alcian blue + hyaluronidase [[5]]. Antibodies that appear to be valuable for the differentiation between mosothelial (reactive or malignant) and epithelial cells include the epithelial markers carcinoembryonic antigen (CEA), Leu-M1 (CD15), Ber-Ep4, MOC-31, B72.3 (anti-TAG 72) and other antibodies against carbohydrate antigens [[5], [7–9]]. Markers considered to be mesothelium-specific are desmin, cytokeratin 5/6, calretinin, and, to a lesser degree, HMBE-1 and thrombomodulin [[5], [7–9]]. A thick “bushy” staining of the cell membrane using the anti-epithelial membrane antigen (EMA) antibody and lack of immunoreactivity for desmin are the best markers for the distinction between MM and reactive mesothelium in our experience [[7]].

ELECTRON MICROSCOPY

EM has always had a strong position in diagnosis of normal, reactive and neoplastic mesothelial cells [[10]]. Ghadially has among many others outlined the characteristic features and discussed the differential diagnosis of carcinomas and sarcomas [[10]]. Zu et al. [[11]] reported a case of an aggressive poorly differentiated mesothelioma with long microvilli.

More recently Ultrastructural Pathology has presented various subtypes. Deciduoid mesothelioma [[12]] has abundant classical surface microvilli. In the series of 5 cases presented by Shia et al. [[12]], other ultrastructural features were variable. Di Muzio et al. [[13]] discussed basal lamina reduplication in malignant epithelioid mesothelioma of the pleura. They reported reduplication in 48% of the epithelial subtype group and in 0% in peripheral adenocarcinoma of the lung. The authors stressed the need for further studies to evaluate the prognostic significance and the importance of EM in the differential diagnosis in lung/pleural tumors.

In the present issue of Ultrastructural Pathology, Yao et al. [[14]] present 4 cases of the lymphohistiocytoid mesothelioma. The cases were selected from a series of 120 mesotheliomas. Three of the 4 cases were presented with focal mesothelioid differentiation. These tumors, strongly infiltrated with lymphocytes and with a diffuse proliferation of histiocytoid looking cells, can be a diagnostic challenge. All cases reported so far (10 in total) were present in the pleura.

Malignant mesothelioma is well known to present various faces. It can be a challenge to establish a correct diagnosis and EM is continuing to be an important tool also in identification of the more rare variants.