Epithelial Mesothelioma - Epithelial Mesothelioma Cells
Pleural Mesothelioma
Chest pain or dyspnea is almost constant, although of varying degree.63,214 Pleural effusion is present initially in up to 95% of cases.63 Later, tumor growth usually results in complete obliteration of the pleural space and encasement of the lung.93,214,264 Cough, weight loss, and fever are not uncommon. In contrast to benign mesothelioma, clubbing is rare and was seen only in 6% of cases.51 Mediastinal invasion with dysphagia, phrenic nerve paralysis, pericardial effusion, and superior vena cava syndrome can occur.225 Spontaneous pneumothorax or hydropneumothorax and Horners syndrome have been described.127,206 Progressive invasion of the chest wall often leads to intractable pain.
Chest radiographs reveal a variable amount of fluid, with pleural thickening or pleural nodules, often several centimeters in diameter, imposing a scalloped appearance (Fig. 89.2). Predominance at the base is almost constant. In advanced cases, ipsilateral shift of the mediastinum and retraction of the involved hemithorax are characteristic, unless the tumor volume becomes very large.63,93 The electrocardiogram (ECG) is abnormal in almost 90% of patients, showing various arrythmias (sinus tachycardia is the single most common change [42% of cases] but also premature atrial or ventricular contractions, atrial fibrillation, or flutter), conduction abnormalities (right-side bundle branch block, left hemiblocks), nonspecific ST-T changes, or left or right hypertrophy.289
Computed tomography (CT) is most valuable in showing the extent of disease (including chest wall, carmine and strongly with colloidal iron or Alcian blue and disappears after preincubation with hyaluronidase.258 The detection of hyaluronic acid is important in the differential diagnosis of mesothelioma, particularly adenocarcinoma, with two reservations: (1) hyaluronic acid may be dissolved in formalin-fixed tissue because it is water soluble, and (2) hyaluronic acid is not specific since it is found also in any rapidly growing tumor containing young connective tissue stroma. Its presence, thus, is of diagnostic importance only for the epithelial type.69 Its detection in the tumor cell, however, rather than in the stroma is highly suggestive of mesothelioma. On the other hand, mesotheliomas do not usually produce mucin but may contain glycogen. Mucicarmine stain is typically negative.
The periodic acidSchiff reaction, after removal of glycogen by diastase (DPAS), detects neutral mucins and is likely to be positive in adenocarcinoma and negative in mesothelioma.303 Whereas keratin stains were positive in 86 to 90% of mesotheliomas and 95 to 100% of lung adenocarcinomas,271,303 vimentin was detected in 86% of the former and none of the latter.303 A major problem with vimentin, however, is its detection in normal mesenchymal cells.303 Other useful stains to differentiate epithelial mesothelioma from adenocarcinoma include (1) carcinoembryonic antigen (CEA), usually totally negative or faintly positive in less than 10% of mesotheliomas, compared with 91 to 95% positivity in lung adenocarcinomas; and (2) Leu M1 stain, positive in less than 5% of mesotheliomas but in 80 to 90% of lung adenocarcinomas.271,303
On the other hand, both human milk fat globulin and epithelial membrane antigen are commonly found in both types of neoplasms and are of little value. In summary, a battery of special stains including alcian blue before and after hyaluronidase, mucicarmine, DPAS, CEA, and Leu M1 are most useful (Table 89.1). These special stains are often necessary to distinguish pleural mesothelioma from adenocarcinoma of the lung, particularly in its 'pseudomesotheliomatous" form,121 or peritoneal mesothelioma from adenocarcinomas of the digestive tract or the ovary.
The differential diagnosis of peritoneal mesothelioma from ovarian cancer may be particularly difficult even after special stains; in vitro data suggest that mesothelial cells may also produce the ovarian cancer marker CA 125.277
Studies using antimesothelial antibodies, either polyclonal86 or monoclonal,191,250,308 are in progress and may prove to be useful, if their specificity is shown to be good. Differentiating mesothelioma from adenocarcinoma is clinically important since it may influence the treatment and help avoid a lengthy, costly, and vain search for another primary lesion. Electron microscopy is helpful in doubtful cases, revealing typical microvilli on epithelial mesothelioma cells (the fibrosarcomatous cells lack them) which are longer and thinner than in adenocarcinomas, as well as tonofilaments and cell junctions.258 Cytology has often been disappointing, both in identifying mesothelioma cells and in differentiating them from other tumors or from reactive mesothelial cells.258
Recent studies have emphasized features such as cellular aggregates (morulae), cannibalism and multi-mediastinum, pericardium, and diaphragm), relative amount of fluid and tumor, involvement of interlobar fissures, and retraction of the involved hemithorax (Fig. 89.3). In addition, signs of asbestos exposure, such as contralateral pulmonary fibrosis and/or pleural plaques, are seen in 50% of cases and pleural calcifications in 15%.202 Further studies are needed to evaluate the role of magnetic resonance imaging (MRI). MRI has been better than CT in showing tumor spread into the fissures, diaphragm, and bony structures, whereas both procedures are equally effective to detect invasion into the chest wall, lung, and mediastinum.
145a Echocardiography is useful to reveal pericardial involvement, especially if cardiac tamponade is suspected.289 Uptake of gallium 67GA citrate by mesothelioma tumors has been experimentally demonstrated,273 and gallium scan was positive in 43 of 49 patients (88%) with pleural mesothelioma.265 Recently, the role of fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging has been examined in a cohort of 28 patients with suspected mesothelioma (confirmed in 22).26b
Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. The mean SUV of the deceased patients was 6.6 +/- 2.9, compared with 3.2 +/- 1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study. The survival distribution of the high-SUV group showed significantly shorter survivals, compared with the low-SUV group. Bronchoscopy is usually normal or reveals extrinsic pressure.206
Thoracocentesis yields a serous to viscous, glutinous fluid, which is occasionally frankly bloody.206 The fluid is an exudate, and pleural fluid glucose can be low, but this finding is nonspecific.264 The best positive marker for malignant mesothelioma is the detection of a high level of hyaluronic acid in the fluid,216,217 but this technique is not yet routinely available. Cytologic studies in large series reveal malignant cells in 16 to 38% of patients, but their exact nature is often undetermined or misclassified, and they are diagnostic in only 3 to 16% of patients with mesothelioma.1,225 Greater awareness of the disease, increasing expertise, and use of special stains or electron microscopy may improve these disappointing results. Pleural needle biopsy shows malignant disease in 13 to 48% of cases, and a diagnosis of mesothelioma in 10 to 36%.1,225
Use of Tru-cut needles or CT-guided pleural biopsies need more evaluation.170 Thoracoscopy is a useful technique in cases where it is technically possible, yielding a diagnosis of mesothelioma in 70 to 80% of cases170,225 and false-negative results in up to 20% of cases,179 although it was diagnostic in virtually all patients in another study.31,33 Otherwise, thoracotomy with open surgical biopsy remains the best diagnostic procedure, yielding the diagnosis in 77 to 100% of patients.1,225
There is a lack of positive serum markers currently available for the diagnosis of mesothelioma. Serum CEA and alpha-fetoprotein (AFP) values are usually within normal limits.52 The detection of an elevated serum level of hyaluronic acid may prove useful in differentiating mesothelioma from other tumors,76 or to follow the effect of treatment.
77 In an experimental model of human mesothelioma transplanted in nude mice, serum levels of hyaluronic acid became detectable within 4 days after subcutaneous transplantation, before the tumors in mice were palpable.216 Serum immunoglobulins show no specific pattern.52
Median survival is about 10 to 17 months from onset of symptoms and 9 to 13 months from diagnosis.58,63,127,225 The 3- and 5-year survival probabilities were 10 and 3%, respectively, in one review of 92 cases,1 and 5.6% for 5-year survival in another review of 123 patients.39