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