115: Pathology of Pleural Malignant Mesothelioma

Malignant mesothelioma (MM) is an uncommon disease with approximately 3000 new cases diagnosed each year in the United States. Most occur in the pleura. However, each year about 300 new cases occur in the peritoneum and many fewer in the pericardium and paratesticular serous membranes. Although most persons with pleural malignant mesothelioma (PMM) are middle-aged males (median 62 years), the disease also occurs in lesser numbers of women and over a wide age range. The presentation is usually with dyspnea secondary to a pleural effusion and/or chest wall pain. Most give a history of occupational exposure to asbestos 20 to 40 years or more earlier. Pathologic diagnosis guides treatment and is generally based on a pleural biopsy obtained by VATS. Prognosis is poor in most cases with few surviving 2 years following diagnosis. However, some recent reports indicate palliation with therapy and present studies aim at cure. This article will focus on the critical role pathology plays¹ as it interfaces with surgery, radiology, and oncology in the management of PMM. We will consider surgical pathology procedures and tissue collection, classification, differential diagnosis, prognostic factors, grading, and causation and pathogenesis of PMM.

Important elements in the pathologic diagnosis of PMM are the clinical history, especially the presenting symptom, any history of past or present tumor and relevant radiologic features, especially those seen in the chest x-ray, CT, and/or PET scan. Diffuse nodular pleural thickening or a pleural-based mass are characteristic of PMM. However, in some cases, tumor nodularity is lacking and the pleura is thickened by diffusely fibrotic tumor.

Cytologic examination with cell block examination of pleural fluid is usually one of the first steps after radiologic examination in the workup of patients suspected of PMM. Cytologic examination may establish a diagnosis of adenocarcinoma. In other cases atypical, or even frankly malignant mesothelial cells, may be present. Fluorescence in situ hybridization (FISH) and immunohistochemical studies of pleural fluid specimens may help to establish a malignant diagnosis in some cases. However, tissue invasion, required for the pathologic diagnosis of PMM, is not feasible in pleural fluid specimens. Pathologic diagnosis may be based on a fine needle aspirate or core biopsy, but usually requires examination of a VATS biopsy, or rarely, an open biopsy.

Frozen Section Examination

PMM usually begins in the parietal pleura, rather than in the visceral pleura. This is supported by several observations including those in a thoracoscopic and pathologic prospective study of biopsies of 188 early cases of PMM, which revealed that patients whose tumor was confined to the parietal pleura survived significantly longer (median survival time 32.7 months) than those with involvement of both parietal and visceral pleura (median survival time 7 months). No instances of tumors involving only visceral pleura were encountered.² Tumor first appears on gross examination as tiny, 1 to 2 mm gray–white nodules studding the surface of the parietal pleura (Fig. 115-1). Thereafter, tumor nodules enlarge, tumor spreads to the visceral pleura, and visceral and parietal pleural thickening and fusion ensue.³ Most pleural biopsies are of the parietal pleura. Distinguishing invasive PMM from other lesions on gross examination may be difficult.^4–6 Invasive PMM is characterized by firm, nodular or plaque-like, gray–white thickening of the pleura (Fig. 115-2). In contrast, hyaline pleural plaque, usually identifiable first on radiologic examination, is densely collagenous, hard and white, often has a shelf-like border, and may be focally calcified (see Fig. 115-1). Chronic fibrosing pleuritis also thickens the pleura, is firm and gray–white, and often diffuse. It may be difficult to distinguish from the sarcomatoid type of PMM (SPMM), both grossly and microscopically; such cases often require extensive sampling to separate from PMM. Metastatic adenocarcinoma occurs more often in the pleura than PMM and is not distinguishable on radiologic or gross examination. Pleural biopsies are submitted for intraoperative FSE in cases of suspected PMM to establish the presence of tumor in the biopsy. The biopsy should confirm that the tissue taken is adequate for subsequent permanent section examination and diagnosis. Distinction of PMM from metastatic adenocarcinoma is not possible by FSE. PMM is often heterogeneous on histopathologic examination and small biopsies may not be representative.¹ Generous pleural biopsies should be taken, both for diagnosis and for accurate histopathologic typing. The latter provides valuable prognostic information that is utilized in planning therapy. Larger tissue biopsies also may provide nonfrozen tumor for permanent section examination, thus avoiding frozen artifact in the tumor cells that may impede morphologic interpretation and alter immunohistochemical test results. Small portions of tumour in biopsies, fixed promptly in appropriate fixative in the FS room, are recommended to facilitate optimal electron microscopic (EM) examination. EM examination may help to establish a diagnosis, especially in controversial cases. Wedge biopsies to include visceral pleura and biopsies or excisions of lung, chest wall, mediastinal nodules, or other masses suspicious for PMM are occasionally submitted for FSE. They are examined and processed as noted above for pleural biopsies.

Debulking procedures performed to remove grossly visible PMM include Pleurectomy (PP), Parietal Pleurectomy and Decortication (PPD), Extended PPD with resection of diaphragm and/or pericardium, Chest Wall Resection with resection of rib(s), and Extrapleural Pneumonectomy (EPP). In EPP, resection includes parietal and visceral pleura, an entire lung, a portion of pericardium and the ipsilateral hemidiaphragm (Fig. 115-3).

FSE may be utilized to examine margins, and tumor tissue is often taken for special studies, including snap freezing for organ bank preservation. However, the specimens, including pleural, diaphragmatic, and pericardial margins, are usually examined by the pathologist after lung perfusion, fixation, dissection, and extensive tissue sampling, and are performed in the surgical pathology area.^1,6 Digestion studies for quantifying asbestos bodies of fibers in the lung or other tissues may be performed on paraffin tissue blocks. However, it is recommended that formalin-fixed, wet lung tissue (5–10 g) be taken from the periphery of upper and lower lobes and stored as a ready tissue source for quantitative asbestos body/fiber analysis.

Mediastinoscopy with lymph node biopsy, usually performed after a PMM positive pleural biopsy is diagnosed, is a staging procedure; positivity is an adverse prognostic event. Most nodes are not submitted for frozen section examination (FSE); they are best processed for permanent section pathologic examination. However, nodes suspected of infectious disease, or portions thereof, are submitted for culture as well as for permanent section pathologic examination.

Pleural mesothelioma is generally considered to be both malignant and diffuse. However, a localized form of PMM (LPMM) that is also malignant has been described and is considered here. It is important to recognize because it has a likelihood of better survival than the diffuse form. Furthermore, a rare form of mesothelioma, previously thought to be restricted to the peritoneum, has been described in the pleura as well differentiated papillary mesothelioma, a solitary or multifocal tumor which has a benign or indolent course. Thus it deserves distinction from the much more common diffuse PMM.

Histopathologic Types

The most widely utilized classification of PMM is a histopathologic classification based on microscopic examination of formalin-fixed, hematoxylin and eosin (H&E) stained tissue sections. The three types of diffuse PMM, recently categorized as subtypes,⁴ are epithelial (or epithelioid), sarcomatoid (or sarcomatous), and mixed (or biphasic) (Table 115-1). Histologic features of these subtypes are illustrated in Figure 115-4. The most common type of PMM is epithelial (55% in a large series) with lesser numbers of the mixed type (24%) and of the sarcomatoid type (22%).⁴ A desmoplastic malignant mesothelioma is a MM with extensive dense stromal fibrosis (Fig. 115-4D). Usually, but not always, it is of the sarcomatoid type.^1,3–5,7 It is usually classified as a form of sarcomatoid MM, and has a very poor prognosis.

Histopathologic classification by type of PMM is relied on to predict survival, and aid in choosing the course of treatment. Those with epithelial type PMM (EPMM) have the best survival, and those with SPMM, the worst. Mixed forms (MPMM) have a survival intermediate between the other two types. Those with SPMM also are unlikely to exhibit positive cytology on examination of pleural fluid and less likely to respond to multimodality therapy than the other types.

Epmm Variants

EPMM's exhibit numerous histopathologic patterns and most are polymorphous, exhibiting several patterns. These patterns, which have been described as subtypes, variants, categories, and morphologic forms, will be referred to herein as variants. The variants are based on architectural features, for example, tubular, papillary, or solid; or cytologic features, for example, small cell, signet cell, or deciduoid cell; or stromal, for example, desmoplastic or myxoid. The variants aid in establishing the histopathologic diagnosis. However, they seldom contribute useful prognostic information and hence, are not included in the pathologic diagnosis. More than 20 variants of the epithelial type have been identified.^4,5 The most common variants of the epithelial type variants are tubulopapillary, solid, and microcystic (adenomatoid). An uncommon high grade (undifferentiated) pleomorphic variant of EPMM has been described. It is comprised of clusters and sheets of large, pleomorphic, round cells with hyperchromatic nuclei, frequent mitoses, and necrosis. It resembles a large cell or undifferentiated carcinoma, but may be distinguished by its immunohistochemical reactivity or sometimes by its EM features. Variants of the mixed and sarcomatoid types are far fewer that those of the epithelial type. A few variants have been reported recently to have prognostic value. The myxoid variant was reported to have a prolonged survival (mst. 30 months)⁸ and the high grade pleomorphic variant of the epithelial type was reported to have a significantly worse survival than other variants of this histopathologic type.⁹ In this large study, 232 cases of EPMM were classified as one of five subtypes. In multivariant analysis, the 34 classified as pleomorphic had an overall worse prognosis (8.1 months survival, p < 0.001), compared with the other four subtypes with survivals of 15.8 to 24.9 months; subtype also was an independent predictor of poor survival. Pleomorphic EPMM had a near identical survival curve to the MPMM and no significant difference in overall survival with SPMM, leading the authors to suggest their reclassification to mixed or sarcomatoid type.

It is important to recognize that survival of PMM also varies with pathologic stage. A reliable pathologic staging system is an essential requirement for accurately predicting survival of those with one or more of the many histopathologic variants of PMM.

Localized PMM

LPMM is a rare entity in which the tumor is confined to a solitary pleural mass, of average size about 6 cm (see Fig. 115-2C). The histopathologic, immunohistologic, and EM features are those of PMM; thus, the tumor cannot be distinguished from PMM solely by pathologic examination of a pleural biopsy, but requires careful consideration of radiologic and surgical findings. All three histopathologic types of PMM may occur in LPMM, however, unlike PMM, there is no difference in survival among the three groups. LPMM may recur and metastasize, but diffuse pleural spread does not occur. Importantly, it has a better prognosis than PMM; the largest series reports that 10 of 21 patients with follow-up data were alive and without evidence of recurrence, 18 months to 11 years after diagnosis.¹⁰ However, before concluding that a mass is LPMM, the evidence supporting the localized nature of the PMM should be scrutinized carefully.

Well Differentiated Papillary Mesothelioma (WDPM)

This uncommon papillary epithelioid tumor, which usually occurs in the peritoneum of middle aged women, may occasionally arise in the pleura in a solitary or multiple form.^4,5 Solitary tumors incidental to thoracoscopy or thoracotomy that lack clinical symptoms and effusion attributable to the tumor, and meet certain other criteria are considered benign. The additional criteria are that they are comprised of papillary or club-shaped processes with fibrovascular cores that are covered by a single layer of bland cuboidal mesothelial cells and invasion is not present.⁵ Multiple pleural papillary tumors with characteristic histopathologic features of WDPM, pleural effusion or thickening, and minimal or superficial invasion usually pursue a more indolent course than PMM. Rare cases of PMM may contain WDPM-like foci. In such cases, survival of the PMM may be modified, depending on the proportion of the WDPM-like foci in the invasive PMM.

Sarcomatoid PMM (SPMM)

H&E stained sections of this type of PMM reveal spindle cells in a fibrous stroma, separable from the spindled normal pleural stromal cells by the atypical nuclear features and hypercellularity of the tumor cells.^3–5,11 One common pattern in many SPMMs is of small spindled tumor cells with densely hyperchromatic nuclei that vary in size and shape and are arranged in sheets, or form short fascicles. In another common pattern of SPMM, the spindled tumor cells are large and plump with vesicular nuclei, resembling so-called malignant fibrous histiocytoma (undifferentiated spindle cell sarcoma) (Fig. 115-4C). In both variants, interlacing or storiform architectural patterns and necrosis often are present.

Desmoplastic PMM,^3–5 usually occurs as a variant of sarcomatoid mesothelioma and has a poor prognosis. By definition, it contains densely collagenous, hypocellular fibrous tissue with bland nuclei involving 50% or greater of the tumor area. It may be extremely difficult to recognize on FSE due to lack of malignant features such as hyperchromatism, pleomorphism, and hypercellularity in the tissue sampled (Fig. 115-4D). Thus, multiple biopsy samples and pathologic examination of abundant tissue may be required to establish the diagnosis. The presence of a storiform or “patternless” fibrous pattern, and other features, including frankly sarcomatoid areas, or demonstrable invasion of chest wall tissue, for example, invasion of extrapleural adipose or skeletal muscle, serve to distinguish it from its mimic, chronic fibrosing pleuritis (organizing pleurisy, fibrous pleurisy).⁴

Several other variants have been described that are important to recognize; some cases have been diagnosed initially as lymphoma. These include Lymphohistiocytoid PMM, a rare variant constituting less than 1% of MM's, with morphologic features suggesting a lymphoma.^4,5 The prognosis was reported initially to be similar to that of SPMM. However, a recent study of 22 cases reported a prognosis similar to that of EPMM.¹²

Transitional PMM is a rare variant with morphologic features of both EPMM and SPMM^4,5 and a prognosis, based on limited studies, similar to SPMM.⁴ Another variant contains heterologous elements, notably osteosarcomatous, chondrosarcomatous, and/or rhabdomyoblastic elements. This variant has clinical, histopathologic, and immunohistochemical features of PMM, but in addition, one or more heterologous elements. In a series of 27 cases, 16 were of sarcomatoid type, 12 were mixed type, and only 1 was EPMM.¹³

The MPMM is comprised of both EPMM and SPMM. The WHO classification of MM defines mixed types as those in which each component represents at least 10% of the tumour.⁷ Other experienced pathologists include as mixed types those in which the putative minor component is clearly definable, regardless of its proportion of the tumor in the specimen. The proportion of the epithelial and sarcomatoid element in the PMM appears to be predictive of survival, with the predominantly epithelial type having the better prognosis. Biopsy specimens often do not accurately reflect the proportion of the types of PMM present in the tumor, owing to the polymorphous nature of PMM and the unequal representation of the epithelial and sarcomatoid types in various areas of the tissue. The most accurate predictions of survival come from analysis of larger specimens, such as those from extrapulmonary pneumonectomy, pleurectomy, and chest wall resection.

The distinction of PMM from other tumors is based on evaluation of the clinical, radiologic, and pathologic features. Presenting symptom, history of past or present tumor of other sites, radiologic findings, especially of chest CT and PET scan, and findings at surgery may aid in the distinction. Also, adequacy of the pleural biopsy (see Surgical Pathology Procedures and Tissue Collection) may abet pathologic diagnosis and tumor classification. Morphologic classification based on histopathologic examination and immunohistochemical staining play key roles in the distinction (Fig. 115-5). Furthermore, the results of histochemical stains and/or EM examination also are critical in some cases. Recently, FISH and/or molecular genetics have assumed increasing roles in establishing the pathologic diagnosis, for example, FISH when the DD is atypical mesothelial hyperplasia; FISH and molecular genetics when the DD is synovial sarcoma.

The separation of PMM from other tumors of the pleura is closely linked to the histopathologic type of the PMM. The DD of EPMM, which is tabulated in Table 115-2, includes atypical mesothelial hyperplasia and many tumors of primary and metastatic origin. Some of the carcinomas and sarcomas, as well as the rare thymic tumors, may be either primary or secondary. The most common distinctions to be made with diffuse PMM of epithelial type are with atypical mesothelial proliferation and with metastatic adenocarcinoma. Others may be problematic, in part, due to their rare occurrence.

Atypical Mesothelial Proliferation

Proliferations of the squamoid (flat) or cuboidal mesothelial cells that line the pleura have been classified as reactive mesothelial hyperplasia, atypical mesothelial hyperplasia, atypical mesothelial proliferation, and MM in situ.^4,5 This morphologic assessment is based on proliferation of cells with atypical cytologic features, including nuclear hyperchromasia and irregularity of surface cells, and surface mesothelial cell stratification and/or papillary formation. It is important to note that the sequence from hyperplasia to carcinoma that obtains in organs, such as colon and cervix, has not been established for mesothelial cells. Hence, a diagnosis in surface proliferations of MM in situ is reserved for cases in which there is clear evidence of established malignancy, that is, microscopic evidence of bulk tumor on the pleural surface or definite invasion of underlying tissue. Hence, the diagnosis of mesothelioma in situ is considered appropriate only when accompanied by invasive MM.^4,5,14 The distinction between AMP and EPMM may be very difficult on occasion. Pathology consultation, rebiopsy and/or careful follow-up afford several alternatives to the overdiagnosis of EPMM. Recent evaluations of FISH testing performed on paraffin embedded cell blocks or tissue for the presence of homozygous p16 deletions in PMM suggest that such testing may help to distinguish between diffuse PMM and AMP (see section on Cytogenetics and Molecular Genetics, below).

Metastatic Adenocarcinoma

Most of the problems in separating EPMM from its mimics occur in distinguishing it from adenocarcinomas metastatic to the pleura, a much more common occurrence than primary EPMM.^3–5 The most common primary sites of the metastatic carcinomas are lung, breast, ovary, prostate, colon, stomach, kidney, and thyroid gland. Pathologic distinction of PMM from its mimics is based upon clinical information and both conventional H&E and special pathologic tests. For example, the history of the organ site of a known carcinoma may help in selecting the best panel of antibodies for immunohistochemical testing. Histochemical tests for mucins, including mucicarmine, D-PAS, and hyaluronidase alcian blue, utilized for many years, have been replaced largely by immunohistochemical tests of greater sensitivity and specificity. EM examination is not widely used now, but may be invaluable in some cases, especially if tissue has been appropriately fixed at the time of biopsy.

Immunohistochemical tests, performed on paraffin embedded tissue sections, are widely employed for the distinction of adenocarcinoma from EPMM, which has a different immunohistochemical phenotype. However, no single antibody possesses adequate sensitivity and specificity to consistently distinguish PMM and adenocarcinoma. Therefore, panels consisting of a number of antibodies are employed. A panel consisting of two positive and two negative markers for mesothelioma is recommended. Additional antibodies are employed when results are inconclusive. Variation of sensitivity and specificity vary with the laboratory, requiring performance validation of the antibodies employed by each laboratory. Our antibody panel for the distinction of EPMM and adenocarcinoma consists of five antibodies. AE1/AE3 keratin antibody is positive in essentially all EPMM cases (Fig. 115-5A), thereby excluding from the differential diagnosis essentially all metastatic melanomas and lymphomas, excepting ALK positive, large B cell lymphoma. Most adenocarcinomas are also positive. However, the perinuclear-predominant pattern of cytoplasmic staining of mesotheliomas in most cases helps to distinguish them from adenocarcinomas, which typically have a membrane predominant pattern. The two mesothelial positive markers in our panel are calretinin (Fig. 115-5C) and Wilms Tumor Protein-1 (WT-1) (Fig. 115-5E and F). Calretinin is positive in more that 90% of EPMM, and is negative, or only weakly positive in most adenocarcinomas. WT-1 is also present in more than 90% of EPMM's in a nuclear staining pattern, but is also positive in many ovarian serous carcinomas, including those metastatic to the pleura. However, the addition to the panel of PAX 8, positive in most serous adenocarcinomas of the ovary, but negative in PMM, helps in the DD cases of possible metastatic adenocarcinoma in women. Other antibodies employed as positive mesothelioma markers that have been employed include keratin 5/6, thrombomodulin, mesothelin, and D2-40. The two negative markers in our panel are CEA (Fig. 115-5D) and TTF1. CEA is positive in about 75% of metastatic adenocarcinomas, but is negative in adenocarcinomas of the kidney, prostate, and many carcinomas of the thyroid and ovary. In contrast, positive polyclonal CEA staining in mesotheliomas in our laboratory is negative in almost all EPMM. TTF1 is positive in about 70% to 75% of adenocarcinomas of the lung, but is negative in PMM in our laboratory. Negative markers for mesothelioma that have been employed include CD15, BG-8, B72.3, Ber-Ep4, TTF-1, and MOC-31.

Epithelioid hemangioendothelioma (EHE) is a low to medium grade malignant vascular tumor that may occur as a primary or metastatic tumor in the pleura, or as an extension of a lung primary. It may be indistinguishable from EPMM on radiologic examination and on gross and H&E microscopic examination. Histopathologic clues to its possible presence are weak or moderate keratin immunoreactivity and calretinin negativity. It is positive for one or more vascular markers: CD31, CD34, Fli-1, or Factor VIII.

Metastatic renal cell carcinoma (RCC) may be difficult to distinguish from PMM. A recent review concludes that it is important to include at least CD10, RCC marker, PAX2, and PAX8, as positive markers for RCC, in the diagnostic panel.¹⁵

EM examination of EPMM^3–5 may be helpful in cases with discordant immunohistochemical features, unusual subtypes or poor differentiation. The detection of numerous long, thin, curved microvilli which project from the surface of the cell or into an intracellular lumen, distinguish EPMM from adenocarcinoma. However, the characteristic microscopic villi usually are absent in poorly differentiated EPMM and in SPMM.

In summary, immunohistochemical tests have greatly improved the diagnostic accuracy in PMM. However, consideration of clinical, radiologic and operative features still is important. EM and/or histochemistry may be of help in some cases; some pathologists still rely routinely and heavily on EM. Additional biopsy leads to a definitive diagnosis in some controversial cases.

Differential Diagnosis of SPMM

Included in the differential diagnosis of the sarcomatoid type are benign and malignant tumors and primary and metastatic tumors (Table 115-3).^3–5,11

Calcific fibrous tumor is a benign tumor that usually occurs in soft tissues, but a few occurring in the visceral pleura and mediastinum have been reported. They may be solitary or multiple, forming a mass up to 12 cm. Dystrophic or psammomatous calcifications, which may be visible on CT scan, are scattered in a collagenous fibrous stroma that is lightly infiltrated by small lymphocytes. Stromal cells are negative for AE/AE3 keratins and CD34, helping to distinguish this tumor from PMM and solitary fibrous tumor (SFT).

Synovial sarcoma may occur in the pleura a primary tumor, as well as metastatic tumor or by extension from a lung primary.^4,5,7 The monophasic spindle cell type of synovial sarcoma, which is in the differential diagnosis of SPMM is usually present as a solitary mass, but diffuse involvement also occurs. On microscopic examination, the cells are usually small, spindled, closely packed, and arranged in interweaving fascicles, a so-called stream of fish pattern, rarely seen in SPMM. AE1/AE3 keratin, usually weak and focal, is present in about two thirds of cases, and it is less extensive than that seen in most cases of sarcomatoid mesothelioma. Cytogenetics in about 90% of cases reveals an X;18 (p11;q11) translocation, considered specific for this tumor. Molecular genetics, using reverse transcriptase polymerase chain reaction (RT-PCR) reveals a SYT-SS1 or SYT-SS2 fusion.

SFT occurs as a benign, occasionally malignant tumor, of the thorax that is thought to derive from submesothelial mesenchyme and is not of mesothelial origin.^4,5,7,11 The usual age range at presentation is the fourth to sixth decade. Most SFT's are discovered as an incidental finding at chest x-ray or CT scan. Rarely, the presenting manifestation is hypoglycemia, secondary to production by the tumor of insulin-like growth factor. Most SFT's are round and smooth-surfaced, with a pushing border and are solitary. They may form a large mass, up to 30 cm or larger. About 80% arise from the visceral pleura, to which they are attached by a peduncle, but others may involve the mediastinum or other intrathoracic sites, including the lung parenchyma. Histopathologic appearance is of bland, slender spindle cells, often in a dense, rope-like collagenous stroma and with branching, staghorn vascular channels. The characteristic immunohistochemical profile is keratin negativity and CD34 positivity. Rarely, malignant SFT's are identifiable by frankly malignant behavior and sarcomatous histopathologic features; however, the prognosis of others with worrisome clinical behavior or pathologic features can be problematic.^4,5

The association of PMM with asbestos exposure is based on landmark epidemiologic studies as well as numerous confirmatory studies including those that quantify asbestos fibers in the lung and tumor (Reviewed in 5,¹⁶). There is no known threshold limit for asbestos exposure below which there is no risk of PMM.¹⁷ Asbestos fibers induce PMM in animals in chronic inhalation exposure studies, and by direct intrapleural or intraperitoneal injection.¹⁸ Other associations, such as SV-40, have been implicated in the causation of mesothelioma, but these suggest possible cocarcinogenic roles.¹⁹ Asbestos exists as two types of fibers, straight (amphiboles) and curved (serpentine). Amphiboles include the following common fiber types: actinolite, amosite, anthophyllite, crocidolite, and tremolite. Chrysotile is the common serpentine fiber; it usually has a tubular structure, and may be soluble in acids. All fiber types are heat and fire resistant and have insulating properties. All forms of asbestos are fibrous silicates, that is, silicon dioxide with various substituted elements. Available evidence suggests that all asbestos fiber types have carcinogenic potential.^5,16

Asbestos bodies (asbestos fibers coated with iron and protein) may be observed either in routine histologic sections of lung tissue in heavily exposed individuals or in lung digestion preparations as illustrated in Figure 115-6 A. Asbestos bodies and uncoated fibers may be detected using scanning EM on sections cut from paraffin-embedded tissue or with digested thoracic tissues using transmission or scanning EM. Energy dispersive x-ray analysis may be used with either type of EM as a means to determine the chemical composition and therefore type of fiber identified (Fig. 115-6B). The tissue quantification of asbestos is a critical link in establishing asbestos exposure as etiologically important in specific cases of PMM, and has been correlated to histological type of mesothelioma, survival with mesothelioma, and degree of epigenetic change in cell cycle related genes.^20–23

Since asbestos has been banned in many countries and its use has declined in most western countries, a decrease in the number of new cases of PMM has been predicted.²⁴ However, worldwide consumption of asbestos remains surprisingly high in some countries, exceeding consumption levels in the United States of the 1950s through the 1970s. China, Russia, Kazakhstan, India, and Thailand are the current leading consumers of asbestos,²⁵ and there is little control as to whether asbestos may be included in any products sold in the West by manufacturers in these countries. At the same time, concerns are being expressed that new man-made fiber-like materials, such as multiwalled carbon nanotubules, may have properties that have response similarities to asbestos.²⁶ Other etiologic factors include irradiation²⁷ and genetic predisposition.^28,29

Pathogenetic mechanisms by which asbestos exposure leads to PMM include: (1) asbestos fibers generate free radicals from their surfaces as well as through interactions with cells; (2) asbestos fibers cause a chronic inflammatory reaction leading to prolonged release of reactive oxygen species (ROS), reactive nitrogen species (RNS), cytokines, and growth factors; (3) asbestos fibers damage DNA and interfere physically with mitosis; (4) asbestos fibers and ROS stimulate proliferation of target cells through cell signaling pathways; (5) asbestos fibers and ROS induce apoptosis in cultured mesothelial cells, but PMM cells are highly resistant to apoptosis, thus providing a mechanism for continued growth of malignantly transformed cells; and (6) epigenetic silencing of tumor suppressor genes provides another mechanism that is consistent with the long latency and time course of this malignancy. A detailed recent review of all of these mechanisms has recently been published.⁵

Cytogenetics and molecular genetics have contributed to our capabilities in PMM diagnosis as well as aided in the understanding of the pathogenesis of this malignancy. PMM has been shown to have detectable chromosomal aberrations, and karyotypic analyses can be used for the distinction between reactive mesothelial cells and PMM. However, there is no consistent specific abnormality found in all cases. PMM's have clonal cytogenetic aberrations indicative of malignancy, of which the more common aberrations include deletions of 1p, 3p, 6q, 9p, and 22q, and trisomy 7, 15, and 16. Table 115-4 lists the cytogenetic abnormalities that have been observed.³⁰ These deletions can be detected by FISH, and they are not observed in benign effusions (Fig. 115-7).³¹ Thus, FISH can be a particularly useful adjunct to cytologic assessment of pleural effusions in the consideration of malignant versus benign effusions. FISH can be performed on fixed, interphase cells using probes to the cytogenetic aberrations.

There is no accepted grading system within types of PMM. Although there are differences in prognosis among different types of PMM as noted above, grading systems for within epithelioid or sarcomatoid tumors are an area of active investigation as research groups have more case material with clinical follow-up from which to try to establish differences among features. Ideally, a grading system for each histologic type is needed; the system should be based upon cases treated with the same therapeutic regimen; and the same pathologic staging system should be used for all comparisons. However, at this time staging system of PMM are also problematic. Staging of PMM is reviewed in detail in Chapter 116. Available staging systems include the first clinical system proposed by Butchart et al. in 1976,³² a modification of that system proposed by investigators at Brigham and Women's Hospital,³³ a tumor-node-metastasis (TNM) based system developed as the International Mesothelioma Interest Group staging system,³⁴ adopted by the American Joint Commission on Cancer (AJCC) in the 6th edition of its Cancer Staging Manual³⁵ and by the International Union against Cancer (UICC)³⁶ which established pathologic staging of PMM in a TNM framework. However, the prognostic utility of the current AJCC/UICC system is limited in that two thirds of patients undergoing EPP with complete pathologic examination of the specimen are classified as Stage III despite a broad range of survival duration. Another staging committee is at work re-evaluating these issues. Meanwhile, Richards et al.³⁷ have used the large mesothelioma database at Brigham and Women's Hospital to suggest data-driven modifications to the current AJCC system which is described in Chapter 116.

High quality pathologic diagnosis allows the best treatment of each individual victim of malignant pleural mesothelioma (MPM). More importantly, pathologic techniques to correctly identify and stage MPM allowed the rapid evolution of disease treatment witnessed over the past 30 years. Being able to distinguish homogeneous groups of patients with the same stage of mesothelioma rapidly expanded the knowledge of a rare disease with only 3000 cases per year diagnosed in the United States. By contrast, there are over 200,000 cases of lung cancer identified in this country yearly. This concise chapter emphasizes the role of the surgeon in providing adequate high quality tissue specimens for H&E stains, FISH, immunohistochemistry, and EM. It describes the methods of differentiating MPM from other differential diagnoses, including chronic fibrosing pleuritis, atypical mesothelial proliferation, primary adenocarcinoma of the lung, metastatic adenocarcinoma, renal carcinoma, and epithelioid hemangioendothelioma. Furthermore, the authors provide a clear discussion of rare mesothelioma variants.