Multiple calcifying fibrous pseudotumors of the pleura: ultrastructural analysis provides insight on mechanism of dissemination.

Calcifying fibrous pseudotumor (CFP) is a rare, benign soft tissue tumor that may uncommonly arise in the pleura. These tumors can show multifocal dissemination across the pleural surface, but the mechanism underlying this dissemination is unclear. Review of previously reported cases of pleural CFP demonstrates a strong predilection for basal and diaphragmatic pleural surfaces, and a significantly higher rate of multifocality compared with other locations. We present a 59-year-old male with multiple CFP of the pleura. Reactive-appearing adhesions spanning the pleural surfaces were present, and by electron microscopy, were involved by tumor. We suggest this is the likely mode of dissemination across the pleural surfaces.

Diagnostic efficacy of electron microscopy and pleural effusion cytology for the distinction of pleural mesothelioma and lung adenocarcinoma.

The diagnosis of malignant pleural mesothelioma (MPM) is challenging and requires immunohistochemistry or electron microscopy assays to specifically differentiate MPM from lung adenocarcinoma. An ultrastructural study of fresh tissue is considered to be the "gold standard." In most cases, the first diagnostic approach is performed on pleural effusion, and in some patients, this is the only available sample for diagnosis. The aim of the present study is to evaluate if an examination of pleural effusion samples based on electron microscopy (EMpe) is a useful tool for the differential diagnosis of MPM and lung adenocarcinoma. An EMpe study was performed in 25 pleural effusion samples. Histological and immunohistochemical markers confirmed the diagnosis of either mesothelioma (5) or adenocarcinoma (20). Of the five cases that were diagnosed with mesothelioma, two samples (40%) showed cells with "bushy" microvilli, which are characteristic of mesothelioma, by EMpe, and three were acellular (60%). Of the 20 cases of adenocarcinoma, EMpe showed cells with short microvilli in 9 (45%), and 11 were acellular (55%). EMpe identifies unequivocal morphological changes that are useful for the differential diagnosis of MPM or adenocarcinoma when the pleural effusion sample contains evaluable tumor cells.

Mesotheliomas with crystalloid structures: report of nine cases, including one with oncocytic features.

Although the presence of crystalloids has historically been of largely academic interest or simply an intriguing curiosity, these structures have occasionally been useful in the differential diagnosis of some tumors. Crystalloids have only rarely been reported in mesotheliomas, and their presence in these tumors has not been sufficiently investigated, nor has their potential value as an ultrastructural marker for mesothelioma been established. The finding of a case of mesothelioma in which the vast majority of the neoplastic cells contained intracytoplasmic crystalloids prompted a search for these structures in 69 consecutive cases of mesothelioma (59 epithelioid, 7 sarcomatoid, 3 mixed-epithelioid sarcomatoid). Crystalloids were found in 9 (15%) of the 59 epithelioid mesotheliomas, indicating that these structures are not as rare as had been thought. That these inclusions were demonstrated in tumors exhibiting diverse histological patterns and were not confined to a single subtype of epithelioid mesothelioma indicates that, because of their unique morphology, when present, they can assist in the diagnosis of these tumors. In addition, oncocytic features were also seen in one of the cases with crystalloid inclusions. Pathologists should be aware of the fact that, even though uncommon, mesotheliomas can present oncocytic morphology and, therefore, these tumors should be included in the differential diagnosis of those neoplasms that display similar morphological features, and which can metastasize to the serosal membranes. To my knowledge, an oncocytic mesothelioma has not previously been reported.

Pleomorphic mesothelioma: report of 10 cases.

Mesotheliomas with pleomorphic features are rare and only a few studies on this mesothelioma variant have been published. Little information regarding the immunoprofile of these tumors and none on their electron microscopic features was included in these studies. Herein are reported 10 cases of pleomorphic mesothelioma that were investigated using a large panel of immunohistochemical markers, 4 of which were also studied by electron microscopy. All of the patients were men and seven had a history of asbestos exposure. Nine of the cases originated in the pleura and one in the peritoneum. Histologically, the tumors were characterized by being composed of large, often discohesive, cells that varied in size and shape, had dense abundant eosinophilic cytoplasm, and single or multiple irregular nuclei, which often contained one or several large nucleoli. Mitotic activity was high and atypical mitoses frequent. Immunoreactivity for pan-keratin and keratin 7 was strong in all of the cases. Expression for calretinin, WT1, podoplanin, mesothelin and keratin 5/6 was also frequent, but variable. All cases were negative for MOC-31, carcinoembryonic antigen, CD15, TAG-72 and thyroid transcription factor-1. Electron microscopy often showed the presence of abundant long, slender microvilli on the cell membrane of the neoplastic cells. These findings demonstrate that, contrary to what has been suggested by some investigators, both immunohistochemistry and electron microscopy can be very helpful in assisting in the diagnosis of pleomorphic mesotheliomas. That the seven patients who underwent extrapleural pneumonectomy had extensive lymph node metastasis and that the median survival of those patients for whom follow-up information was available was only 8.2 months indicates that mesotheliomas with pleomorphic features are associated with highly aggressive clinical behavior. Therefore, when this subtype of epithelioid mesothelioma is present, it should be reported as it can significantly affect the prognosis and treatment of the patient.

Deciduoid mesothelioma: report of 21 cases with review of the literature.

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma that was initially considered to occur exclusively in the peritoneum of young women who had no history of asbestos exposure and to be characterized by an aggressive clinical course, but it was later demonstrated that this tumor could also occur in the pleura of older men and women who had been exposed to asbestos. Some subsequent studies have also indicated that the clinical course is no different from that of conventional epithelioid mesothelioma. Herein are reported 21 cases of deciduoid mesothelioma that were investigated using a large panel of immunohistochemical markers, 9 of which were also studied by electron microscopy. Fifteen of the patients were male and 6 were female (mean age, 60 years). Seventeen of the cases originated in the pleura and four in the peritoneum. Histologically, all of the cases were composed of large, polygonal or ovoid cells with well-defined cell borders, dense eosinophilic cytoplasm, and single or multiple nuclei. In some cases, the cells exhibited a wide variation in their size and shape, frequent loss of cell cohesion, marked nuclear atypia, and high mitotic activity (>5 per 10 HPF); whereas, in others, the cells were more cohesive, less pleomorphic, and the mitotic activity low. As the survival of patients in the first group of cases was shorter (mean, 7 months), when compared with that of the latter (mean, 23 months), it is concluded that the differences in prognosis reported in deciduoid mesothelioma are due to the existence of a high-grade subgroup that presents highly aggressive clinical behavior. Therefore, when a high-grade deciduoid mesothelioma is present, it should be reported as it can significantly affect prognosis and treatment. The use of immunohistochemistry and electron microscopy in assisting in the differential diagnosis of deciduoid mesothelioma is also discussed.

CT imaging of primary pleuropulmonary synovial sarcoma.

AIM: To evaluate the computed tomography (CT) imaging findings of primary pleuropulmonary synovial sarcoma. MATERIALS AND METHODS: Five cases of synovial sarcoma confirmed by histopathology and cytogenetic study were retrospectively analysed. All patients had undergone chest radiography and unenhanced and contrast-enhanced CT examinations, and three had also undergone multiphase CT enhancement examinations. Image characteristics, including shape, size, margin, and attenuation of each lesion before and after contrast enhancement, were analysed. RESULTS: The chest radiographs of the five patients showed well-defined or partly well-defined masses, which were homogeneous and without associated calcification or lymphadenopathy. Pneumothorax was present in one patient. The unenhanced CT images showed well-defined, heterogeneous masses with patchy low density in all five patients. The contrast-enhanced CT images showed heterogeneous enhancement in all cases, three of which demonstrated cystic and necrotic areas. The tumour showed no prolonged or delayed enhancement in three cases using multiphase CT. There were small pleural effusions in four cases. No calcification was observed in any of the cases. There was no evidence of hilar or mediastinal lymphadenopathy. CONCLUSIONS: In these five patients, primary pleuropulmonary synovial sarcoma presented as a well-defined mass with patchy low density and heterogeneous enhancement, with no evidence of regional lymphadenopathy. It should be included in the differential diagnosis of regional tumours.

Pathologic evaluation of malignant pleural mesothelioma.

Pathologists play an important role in the surgical management of diffuse malignant pleural mesothelioma, which relies heavily on accurate diagnosis and staging. The pathologist provides crucial input to the determination of many prognostic factors including histologic subtype, extent of local disease progression, resection margins, and nodal status. They consult with the clinical care team at multiple points along the treatment spectrum, preoperatively, intraoperatively, and postoperatively. Finally, they are increasingly called on to guide selection of chemotherapy and measure treatment response.

Ultrastructural and immunohistochemical analysis of fibrous long-spacing collagen fibrils in malignant mesothelioma.

Three cases of biphasic mesothelioma and 2 cases of sarcomatoid mesothelioma were investigated using light and electron microscopy. In 2 of the 3 cases of biphasic mesotheliomas, fibrous long-spacing (FLS) collagen fibrils were discovered with a symmetrical cross-striation of 130 nm in periodicity. However, no connection between the FLS fibrils and usual collagen fibrils were observed. Periodic acid silver methenamine stain revealed unstained bands with periods of 130 nm in FLS fibrils, whereas the usual collagen fibrils showed continuous positive staining. All 3 cases of biphasic mesotheliomas showed deposits of hyaluronic acid, whereas both cases of sarcomatoid mesotheliomas showed little hyaluronic acid. As a high concentration of hyaluronic acid induces the formation of FLS collagen fibrils in vitro, the authors propose that FLS fibrils from mesothelioma may be special structures that occur as the tropocollagens are assembled into new collagen fibrils in the presence of hyaluronic acid.

[Size distribution of amphibole fibres from lung and pleural tissues sampled from mesothelioma cases due to environmental exposure]. / Caratterizzazione dimensionale di fibre anfiboliche nel polmone e nella pleura di casi di mesotelioma da esposizione ambientale.

BACKGROUND: It has been suggested that malignant mesothelioma might be mainly or only connected with the action of short and ultrathin fibres. On the basis of this hypothesis fibres less than 5 microm long and 0.2-0.1 microm thick would enter the pulmonary-pleura barrier and reach the parietal pleura thus inducing mesothelioma. The hypothesis raised a stimulating scientific discussion. OBJECTIVES: The aim of this communication is to report the initial results obtained comparing the size of amphibole fibres from healthy lung tissue with those from pleural tissue sampled from subjects whose death cause of death was mesothelioma. METHODS: Four mesothelioma cases due to environmental exposure were studied; the fibres were categorized by scanning electron microscopy; for every fibre, length and diameter were measured and the mineral type was defined by its chemical composition determined by X-ray microanalysis. RESULTS: The most important characteristics of the detected fibres were: the average length offibres from the lung and pleural tissues taken from the same subject did not difer, in all cases, by more than 10-12%; 95% offibres found in the lung tissues of all subjects had a length greater than 5 microm; 98% of fibres found in the pleural tissues had a length greater than 5 microm; the average diameter of the fibres found in the pleural tissues was 70% of the diameter of the fibres from the lung tissues. CONCLUSIONS: The experimental data obtained in this study confirm the correlation between malignant mesothelioma and the presence in the lung and pleural tissues of fibres with a length greater, even much greater, than 4-5 microm; thus the hypothesis that the chief factors inducing mesothelioma are the "ultrashort" and "ultrathin" fibres appears rather weak.

[Asbestos fibre lung burden and exposure indices in asbestos-cement workers]. / Carico polmonare di fibre di asbesto e indici di esposizione cumulativa in lavoratori del cementoamianto.

BACKGROUND: In many previous studies, the asbestos fibres retained in the lung were regarded as a good index of cumulative occupational asbestos exposure. Twelve workers suffering from asbestos-related diseases and had been employed in an asbestos-cement factory operating from 1961 to 1994 underwent post mortem investigations in the course of a criminal law suit. OBJECTIVES: Samples of lung tissues were collected for electron microscopy analysis to measure the asbestos fibre burden of the lungs in workers with high exposure, and assess the possible correlation between asbestos fibre lung burden and the estimated levels of cumulative exposure. METHODS: Samples of lung parenchyma obtained from a consecutive series of 12 post-mortem examinations that were performed between 1994 and 2007and included 5 cases of malignant pleural mesothelioma, 4 lung cancers, 1 case of asbestosis and2 ofpleuralplagues, were collected, stored and analysed by SEM electron microscopy, according to the methods suggested by the current scientific literature. For each worker, all males, a detailed occupational history was reconstructed by means ofpersonal interviews; both the measurements of airborne asbestos fibresperformed by the factory in the 1970's and the duration of each single job in the plant were taken into account to estimate an individual cumulative exposure index. RESULTS: A wide variation of total asbestos fibre concentrations in the lung (1,320-118 million) was observed; in all 12 workers, the lung amphibole fibre burden exceeded 1,000,000 fibres per g/dry tissue, The highest values were detected in the mesothelioma cases, in which the mean fibre concentrations differed statistically (t=2.29, p=0.045) from the mean calculated for the other asbestos-related diseases; in 9 subjects only amphibole fibres were detected. There was a good correlation between total asbestos fibre concentration and cumulative exposure index (r=0.91, p<0.0001). CONCLUSION: This study, which was numerically the biggest ever performed in Italy for this category of workers, confirms a wide range of total asbestos fibre burden in heavily occupationally exposed workers and showed that of the asbestos-related diseases, the highest lung concentrations of asbestos fibres were reached in cases of mesothelioma. It was also observed that almost the entire lung burden consists of only amphibole fibres, all exceeding 1 million per gramme of dry tissue. This study tested a synthetic cumulative occupational exposure index, which appears to be well correlated to the level of exposure established by biological analysis.

A biphasic malignant mesothelioma of the peritoneum and pleura in a horse.

This report describes the macroscopic, histologic, immunohistologic and ultrastructural characteristics ofa biphasic malignant mesothelioma in the peritoneal and pleural cavity of a 13-year-old Icelandic pony mare, which exhibited recurrent ascites clinically. Immunohistology was performed employing multiple monoclonal antibodies against cytokeratins (CK) and vimentin. The ultrastructural examination included the quantitative evaluation of the length to diameter ratio of the microvilli. Post mortem examination revealed a severe ascites and hydrothorax. The serosal surfaces of the peritoneum and pleura displayed poorly-demarcated, multifocal to coalescing laminar masses and small nodules. Histology revealed a bimorphic mass consisting of spindle-shaped cells and microcystic epithelioid areas. A transcoelomic and local invasive growth pattern as well as lymph node metastases were noticed. Immunohistology revealed a strong expression of CK. Though a low and moderate expression of CK5/6 and CK20 was present, respectively, CK7 and CK10-antigens were lacking. Ultrastructurally, the epithelioid mesothelioma cells displayed long microvilli, cytoplasmic tonofilaments, and desmosomes. Quantitative evaluation of the length to diameter ratio of the 10 longest microvilli revealed a mean value of approximately 16.2. Summarized, this report described the case of a malignant biphasic mesothelioma with an atypical CK20 expression but a characteristic ultrastructural morphology including long microvilli.

Lipid-rich pleural mesothelioma in a dog.

An 11-year-old, neutered, male Golden Retriever cross dog was euthanized following a history of recurrent pericardial effusions. At necropsy, blood-tinged pericardial and intrathoracic effusions were seen along with numerous firm to hard plaque-like masses that studded the epicardial, pericardial, mediastinal, and costal pleural surfaces. Within the right thorax, the lesions coalesced into a large mass that occupied most of the cavity. Histologically, the masses were composed of solid sheets and papillary aggregates of medium-sized polygonal cells that contained abundant vacuolated to clear cytoplasm. Some of the cytoplasmic vacuoles stained positive with oil red O. The stroma contained metaplastic trabeculae of woven and lamellar bone. Immunohistochemically, the neoplastic cells expressed vimentin, pancytokeratin, and S-100 protein. Transmission electron microscopy corroborated the presence of intracytoplasmic vacuoles and demonstrated prominent intercellular junctional complexes and apically located microvilli. These findings are consistent with a lipid-rich variant of mesothelioma. To the authors' knowledge, this is the first report of a lipid-rich mesothelioma in a dog.

Malignant mesothelioma with intracytoplasmic crystalline inclusions.

A 60-year-old female presented with a history of hoarseness, cough, chest pain, and dyspnea and a needle biopsy sample was submitted for histology. Light microscopy showed sheets of tumor cells with eosinophilic cytoplasm containing multiple crystals and eccentrically located nuclei. Electron microscopy showed large intracytoplasmic crystalloid inclusions. No crystalloid structures were found extracellularly. The tumor cells also had long slender microvilli and cell junctions, the features being consistent with a malignant epithelial mesothelioma. In the authors' experience this is a rare finding. The clinical information initially received was poor and electron microscopy was essential in making the correct diagnosis.

The role of analytical SEM in the determination of causation in malignant mesothelioma.

The causative relationship between asbestos exposure and mesothelioma is firmly established. Some information in this regard comes from analysis of the fiber content of lung tissue by means of analytical electron microscopy. The author has had the opportunity to study the lung asbestos content of 396 cases of mesothelioma, including 28 peritoneal cases, by means of analytical scanning electron microscopy. The highest fiber levels occurred in patients who also had asbestosis, which was found in 12% of pleural and 43% of peritoneal cases. Elevated tissue asbestos content was identified in 87% of pleural and 75% of peritoneal cases. Peritoneal cases that are asbestos related have on average a higher lung fiber burden than pleural cases. Mesotheliomas in women have elevated tissue asbestos content in about 60% of cases, and many of these had a history of exposure as a household contact of an asbestos worker. The main fiber type identified in our series was amphibole, predominantly amosite. These fibers have been demonstrated to reach the target tissue, the pleura.

Macroscopic, histologic, histochemical, immunohistochemical, and ultrastructural features of mesothelioma.

Mesotheliomas are uncommon neoplasms that arise from the cells forming the serosal membranes of the body cavities. Approximately 90-95% of mesotheliomas arise in the pleural cavity and 5-10% in the peritoneal cavity. Rare mesotheliomas arise in the pericardium and in the tunica vaginalis. Unlike many neoplasms, mesotheliomas grow in a diffuse distribution and tend to encase the organs in the various body cavities. A combination of histochemical, immunohistochemical, and ultrastructural features are often necessary to accurately diagnose mesotheliomas. These techniques are highlighted in this review article on mesothelioma.

Transplantation of human malignant mesothelioma into nude mice.

Human pleural malignant mesothelioma was successfully transplanted into nude mice from 2 of 3 patients. The tumor implants of the first generation grew in 6 of 20 mice (30%), with a take of implants of 17 of 32 (53%). Overall, tumors grew from 52 of 80 mice (65%) in a total of 169 of 266 implants (64%) during the first four generations. The mean delay between transplantation and tumor growth was 46 days (range, 18 to 104 days). Pathological examination by light and electron microscopy confirmed the nature of the growing tumors in nude mice. Pathology of transplanted tumors was grossly similar to the human tumors in both first- and second-generation transplants. Up to eight generations have been presently carried out with presence of a human karyotype in transplanted tumors. The potential usefulness of this model with particular reference to chemosensitivity of these tumors will be investigated.

Serum-dependent growth patterns of two, newly established human mesothelioma cell lines.

Two cell lines with different in vitro growth patterns were established from the pleural fluid of a patient with malignant epithelial pleural mesothelioma. The cell line established in RPMI 1640 supplemented with human AB serum had an epithelial morphology, while the cell line established in fetal calf serum-supplemented medium had a fibroblast-like morphology. Exposure of the fibroblast-like cell line to human AB serum-containing medium resulted in a nearly complete transformation of the morphology to the epithelial-like phenotype, and the epithelial-like cell line changed its phenotype to fibroblast-like upon exposure to fetal calf serum-supplemented medium. Both cell lines formed colonies in soft agarose and secreted hyaluronic acid into the culture medium. In both cell lines all the metaphases studied lacked chromosomes 5 and 9, demonstrating the same clonal origin. However, one marker and a missing chromosome 11 were found only in the fibroblast-like cell line. We conclude that human AB serum supplement can be used for the establishment of human tumor cell lines, and that the choice of serum can affect the in vitro morphology of the established mesothelioma cell lines. The mechanisms behind the different growth patterns seem to be a selective stimulation of different subpopulations of malignant cells as well as induction of changes in the morphology of individual cells.

Mesothelioma with clear cell features: an ultrastructural and immunohistochemical study of 20 cases.

Mesotheliomas with clear cell morphology are rare and only a few individual case reports have been documented in the literature. The author reports a series of 20 epithelioid mesotheliomas with clear features, 17 of which originated in the pleura and 3 in the peritoneum. Eighteen of the patients were men and 2 were women. Twelve patients had a history of asbestos exposure. Electron microscopy and special histochemical stains demonstrated that the cytoplasmic clearing seen in hematoxylin and eosin-stained sections resulted from multiple factors that can occur either singly or in combination. The most frequent cause of the cytoplasmic clearing was the accumulation of large amounts of intracytoplasmic glycogen. Another but somewhat less common factor was the accumulation of large amounts of lipid, which occurred alone or with glycogen. Other less common causes were marked mitochondrial swelling, the presence of numerous intracytoplasmic vesicles, and a large number of intracytoplasmic lumens. The value of immunohistochemistry in helping to distinguish epithelioid mesotheliomas from some carcinomas with clear cell morphology is emphasized. In addition, it was determined that because electron microscopy was decisive in establishing the cause of the cytoplasmic clearing in most of the cases, tissue for electron microscopy should routinely be procured for ultrastructural studies.

The value of ThinPrep and cytospin preparation in pleural effusion cytological diagnosis of mesothelioma and adenocarcinoma.

The diagnosis of malignant mesothelioma requires an integration of the clinical presentation, radiological studies, and immunohistochemical stain of histological sections. Cytological diagnosis on pleural effusions of mesothelioma and pulmonary adenocarcinoma is highly desirable but debatable. A spectrum of cytological features has been found to be associated more commonly with malignant mesothelioma (e.g., peripheral cytoplasmic skirt, bubbly cytoplasm, cyanophilic cytoplasm, and scalloped border of cell balls) vs. adenocarcinoma (e.g., two-cell population, inspissated cytoplasmic material, cytoplasmic vacuole, angulated and indented nuclei, and smooth border of cell balls) to only name a few. The current study is designed to assess whether the introduction of a liquid-based technology such as ThinPrep (TP) can provide additional diagnostic value in addition to the conventional cytospin Diff-Quik (DQ) preparations. Pleural effusion specimens were prepared with split samples for DQ-stained cytospin and Papanicolaou-stained liquid-based TP. Fifteen pleural effusion samples with immunohistologically confirmed malignant mesothelioma and 13 pleural effusion samples of immunohistologically confirmed pulmonary adenocarcinomas were retrieved from our files. Both DQ cytospin- and Papanicolaou-stained TP slides were evaluated for the known cytological features associated with malignant mesothelioma (25 cytological features) and adenocarcinoma (22 cytological features) without knowledge of the original cytological and histological diagnoses. The McNemar test was used to compare these two cytological preparations for both malignant mesothelioma and pulmonary adenocarcinoma. In the malignant mesothelioma group, 4 of 25 cytological features evaluated, bubbly cytoplasm (P = 0.002), vacuolated cytoplasm (P = 0.005), cell-in-cell arrangement (P = 0.007) and irregular nuclear contour (P = 0.083), were seen more frequently in the DQ cytospin preparation, as opposed to only one feature, nuclear size enlargement (P = 0.008), more readily seen using TP. In the pulmonary adenocarcinoma group, only 1 of 22 cytological features evaluated, presence of angulated or indented nuclei (P = 0.025), was seen more frequently in DQ as opposed to two features, presence of two- cell population (P = 0.04) and presence of micropapillary structures (P = 0.1), were seen more readily in TP. All other cytological features evaluated distinguishing mesotheliomas (20 features) and pleural adenocarcinomas (19 features) were seen equally readily in both types of specimen preparation techniques. This study suggests that the liquid-based TP preparation of pleural effusions does not appear to provide additional diagnostic value when compared with the DQ cytospin preparation in the cytological distinction between mesothelioma and adenocarcinoma in pleural effusions. Most cytological features evaluated, 20 of 25 (mesothelioma) and 19 of 22 (adenocarcinoma), can be seen in both preparation techniques.

The effects of thermochemotherapy using cyclophosphamide plus hyperthermia on the malignant pleural mesothelioma in vivo.

The human malignant pleural mesothelioma is related to the use of asbestos in the majority of cases. Though the use of asbestos has been prohibited since the 1990s, the incidence of pleural mesothelioma is still increasing because of a latency period of at least 20 years. This study investigated the benefit of single therapy with cyclophosphamide or hyperthermia or the combination of both on cells of a human pleural mesothelioma cell line, xenotransplanted subcutaneously in the paw of mice. A CONTROL group received the same volume of physiological saline. The oxygenation of tumours was measured, tumour growth was followed over 3 weeks, immunohistochemical studies and a light and electron microscopic evaluation were performed. Chemotherapy or hyperthermia alone was only temporarily effective. The greatest benefit was achieved using combined thermochemotherapy consisting of cyclophosphamide plus hyperthermia: 50% of this group had partial remissions, and 67% responded to this therapy. After 3 weeks tumours grew again. Superior effects could be achieved by performing additional cycles of chemotherapy or adding another drug or radiation for instance. This study shows promising results in the treatment of malignant pleural mesothelioma.