Fig. 4.1
Diffuse malignant mesothelioma: The tumor completely encases the lung and extends along the fissure
Fig. 4.2
Diffuse malignant mesothelioma: The tumor at the lower right corner envelop the lung and on the upper field encases the bronchvascular bundle and invade the lung
Microscopically, DMM features a wide range of histopathologic variants. The World Health Organization [7] recognizes three broad basic histologic variants of DMM: epithelial, sarcomatous , and biphasic.
Epithelial Diffuse Malignant Mesothelioma
Epithelial DMM is the most common histologic variant [7], a wide range of morphologic patterns are seen. The most frequent patterns are tubulopapillary, the solid patterns [8, 9, 10], and adenomatoid (microglandular). Sometimes, one pattern predominates but several different patterns are commonly seen in the same tumor. Less common patterns include small cell, clear cell, and deciduoid. Most epithelial DMM is cytologically monotonous and remarkably bland in appearance. The tumor cells are typically cuboidal with moderate amount of eosinophilic cytoplasm with bland and relatively open nuclei and infrequent mitosis (Fig. 4.3). In the less differentiated area, the nuclei show coarse chromatin and prominent nucleoli with frequent mitosis and considerable cell-to-cell variation of such tumor when that pattern predominate the term high-grade (pleomorphic) epithelial DMM will apply (Fig. 4.4). Such tumor is difficult to distinguish from metastatic carcinoma based on routine hematoxylin–eosin (H&E) histology alone.
Fig. 4.3
Epithelial malignant mesothelioma showing cuboidal cells with moderate amount of eosinophilic cytoplasm with bland relatively open nuclei and infrequent mitosis
Fig. 4.4
High-grade (pleomorphic) epithelial mesothelioma showing prominent nucleoli with frequent mitosis and considerable cell-to-cell variation
The most frequent pattern is often referred to as tubulopapillary (Fig. 4.5). In this pattern, the glands and the papillae are covered by a single layer of cuboidal to flattened cells (Fig. 4.6). Psammoma bodies may be seen but are usually infrequent [11] .
Fig. 4.5
Epithelial mesothelioma showing tubulopapillary pattern with outwards secondary branching
Fig. 4.6
Epithelial mesothelioma with tubopapillary pattern shows the glands and the papillae are covered by single layer of cuboidal to flattened cells
Epithelial DMM may show microcytic (adenomatoid; Fig. 4.7) pattern which is usually composed of flattened bland-looking mesothelial cells; careful examination reveals the presence of some cells with large nuclei and prominent nucleoli and the tumor cells show infiltrative and diffuse pattern [12]. Further examination reveals areas of transition to ordinary patterns of epithelial DMM.
Fig. 4.7
Epithelial mesotheliomas with infiltrative microcytic (adenomatoid) pattern composed of flattened bland looking mesothelial cells
Epithelial DMM may also exhibit a predominantly solid sheet-like pattern (Fig. 4.8). In this pattern, the malignant cells form solid sheets of epithelioid cells with abundant eosinophilic cytoplasm with vesicular nuclei and prominent nucleoli; the tumor cells may contain cytoplasmic vacuoles mimicking signet ring carcinoma (Fig. 4.9). The vacuoles are rich in hyaluronate which stain strongly with Alcian blue, pH 2.5, and digested by prior hyalurinidase treatment [13].
Fig. 4.8
Epithelial mesothelioma with solid infiltrative pattern
Fig. 4.9
Epithelial mesothelioma showing polygonal cells with dense eosinophilic cytoplasm and some cells with cytoplasmic vacuoles
The extremely rare small cell pattern [14, 15] of epithelial DMM is composed of fairly small cells mimicking small cell carcinoma of the lung. The mesothelial cells are arranged in monotonous sheets with no crush artifacts or basophilic staining of blood vessels wall. Furthermore, the nuclear chromatin is open with low mitosis. The neuroendocrine markers are usually negative. Further examination of the submitted tissue shows transition to typical patterns of epithelial DMM.
The clear cell [16] pattern shows a loosely arranged sheet of clear cells. Further examination of the tumor reveals areas of transition to more typical DMM patterns. Occasionally, clear tumor cells predominate (Fig. 4.10), and the tumor must be distinguished from metastatic renal cell carcinoma. Immunohistochemical and, if necessary, ultrastructure examination will confirm the mesothelial nature of the neoplastic cells .
Fig. 4.10
Epithelial mesothelioma with clear cell type, this pattern must be differentiated from metastatic renal cell carcinoma
The deciduoid pattern [17–19] consists of large polygonal cells with abundant eosinophilic cytoplasm similar to decidual cells (Fig. 4.11). Sometimes, there is transition from deciduoid form to other typical mesothelial patterns. Immunohistochemistry will confirm the mesothelial origin of the tumor cells.
Fig. 4.11
Epithelial mesothelioma. The tumor show some cells with deciduoid pattern with large cells that resemble decidua
Sarcomatous Diffuse Malignant Mesothelioma
Sarcomatous DMM is an aggressive type of malignant mesothelioma which histologically exhibits a wide range of architectural complexity from hypocellular collections of extremely bland spindle cells to densely cellular areas with obviously high-grade cellular features. The most common pattern consists of closely packed bland-looking spindled cells arranged in fascicles resembling fibrosarcoma (Fig. 4.12) or obviously malignant spindle cells with multinucleated giant cells and a storiform pattern, resembling so-called malignant fibrous histiocytoma (Fig. 4.13). A combination of different patterns may be seen in the same tumor [20–22].
Fig. 4.12
Sarcomatous mesothelioma showing malignant spindle cells with arranged in fascicles resemble fibrosarcoma
Fig. 4.13
A sarcomatous mesothelioma showing the storiform pattern and the high grade nuclei and occasional multinucleated giant cells a typical features seen in sarcomatous mesothelioma
The spindle cells of sarcomatous DMM range from bland spindle cells with a long and thin cytoplasm (Fig. 4.14) to marked anaplasia with bizarre nuclei and increased mitotic figures as shown in Fig. 4.13. In small percentage of cases heterologous elements in the form of malignant cartilage, bone, smooth or skeletal muscles occurmimicking chondrosarcoma, osteosarcoma, leiomyosarcoma, or rhabdomyosarcoma [3, 23–25]. All these are referred to as sarcomatous DMM . Differentiation of sarcomatoid DMM with heterologous elements from primary sarcoma of pleura may be accomplished by focal or diffuse immunohistochemical staining for broad-spectrum cytokeratin (CK) 5/6 and calretinin or ultrastructure examination. There are two additional morphologic variants of sarcomatoid DMM: lymphohistiocytoid variant of sarcomatoid DMM and desmoplastic DMM.
Fig. 4.14
Sarcomatous mesothelioma showing infiltrative relatively bland looking spindle cells with a long and thin cytoplasm
The lymphohistiocytoid variant was first described by Henderson in 1988. [26] This variant of sarcomatoid DMM is characterized by intense chronic inflammatory cell infiltrate of small lymphocytes, plasma cells, and on occasion, eosinophils intermixed with large polygonal to spindle malignant cells with vesicular nuclei and prominent nucleoli (Figs. 4.15 and 4.16). The malignant cells are positive with (CK)5/6 and Calretinin and negative with lymphoma markers. It is important to recognize this variant due to it similarity to malignant lymphoma [27]. The survival of this neoplasm is similar to those of epithelial DMM.
Fig. 4.15
Lymphoepithelioid mesothelioma. The tumor may resemble large cell lymphoma
Fig. 4.16
Lymphoepithelioid mesothelioma. High-power view of the histiocytoid tumor cells intermixed with lymphocytes, a feature which may resemble large cell lymphoma
Desmoplastic DMM is a rare and extremely aggressive variant of sarcomatous DMM [28–30]. This subtype, accounting for approximately 5–10 % of DMM, was first described by Kannerstein and Churg in 1980 [31]. Histopathologic evaluation shows a dense paucicellular hyalinized collagen among which spindle or stellate tumor cells, often associated with slit-like spaces (Fig. 4.17), are arranged in a storiform or patternless arrangement. Sarcomatous foci are usually present and epithelioid foci can occasionally be seen. Diagnosis of DMM requires the identification of characteristic paucicellular, densely collagenous tissue in addition to the presence of frankly sarcomatous areas (Fig. 4.18), in conjunction with one or more of the following features that are considered highly specific for DMM:
Fig. 4.17
Desmoplastic mesotheliomas. High-power view shows the patterns pattern with a dense paucicellular hyalinized collagen among which spindle or stellate tumor cells
Fig. 4.18
Desmoplastic mesothelioma low-power view showing characteristic paucicellular, densely collagenous tissue upper field in addition to the presence of frankly sarcomatous areas in the lower field
1.
Bland infarct-like (no cellular debris or karyorrhexis) sharply demarcated necrosis (Fig. 4.19).
Fig. 4.19
Desmoplastic mesothelioma showing area of bland necrosis in the lower left corner
2.
Invasion of the chest wall adipose tissue or muscle or the lung (Fig. 4.20).
Fig. 4.20
Desmoplastic mesothelioma showing invasion of the chest wall adipose tissue, a feature not seen in fibrosing pleuritis
3.
Presence of expansile nodules, (Fig. 4.21).
Fig. 4.21
Desmoplastic mesothelioma showing presence of expansile nodule in the upper right
4.
Distant metastasis.
Biphasic Diffuse Malignant Mesothelioma
Approximately 20–35 % of DMM are classified as biphasic DMM. This type is frequently identified in pleural DMM patients. Any combination of epithelial or sarcomatous pattern may be present (Fig. 4.22). According to WHO [7], each component must represent at least 10 % of the tumor to meet the criteria for the diagnosis of biphasic DMM.
Fig. 4.22
Biphasic malignant mesothelioma showing an area (upper right) of epithelial and area (Left) of sarcomatous mesothelioma in the same tumor
Differential Diagnosis of Diffuse Malignant Mesothelioma
The differential diagnosis of DMM includes pleural diffuse or localized neoplastic or nonneoplastic (inflammatory/reactive/infectious) processes. The distinction between these entities almost always requires the correlation of clinical, radiographic, gross, microscopic, and immunohistochemical studies. Some differential diagnoses are common and important to discuss.
Epithelial Diffuse Malignant Mesothelioma and Adenocarcinoma
The differential diagnosis between epithelial DMM and lung adenocarcinoma is a well-known diagnostic challenge in surgical pathology, and it is of critical importance for proper medical management. It is also of major importance for legal proceedings that frequently accompany a proposed DMM diagnosis. Both diseases may involve the pleural surfaces and, in most instances, their overlapping histological features preclude a definitive diagnosis based on conventional light microscopic examination. Several ancillary diagnostic techniques, particularly immunohistochemistry , have been employed to assist in rendering accurate diagnoses in these situations [34–36]. The diagnostic utility of conventional histochemical stains alone is limited. Lung adenocarcinomas are not consistently positive for intracytoplasmic mucicarmine and PAS after diastase digestion. Furthermore, false positivity may be observed in a few epithelioid DMM due to technical reasons [14]. The alcian blue-positive, hyalurinidase-sensitive reaction has also been reported in lung adenocarcinomas [15]. Electron microscopy has proven to be useful and is often considered as the gold standard in the diagnosis of epithelial mesothelioma [37, 38]; however, electron microscopic study generally requires great expense and time compared with the other diagnostic techniques, and the morphological ultrastructural features of mesothelial differentiation may not be apparent in the less-differentiated tumors. Furthermore, it may be difficult to obtain. Immunohistochemistry is a generally reliable and typically utilized tool in differentiating DMM from other lesions.
The International Mesothelioma Panel [39] recommends that, at a minimum, two mesothelial and two carcinoma immunomarkers can be used in addition to a pancytokeratin immunostain in rendering a diagnosis. None of these antibodies are 100 % specific and false positives (which often show less than 10 % staining) can occur in any neoplasm. Positive thyroid transcription factor 1 (TTF-1) is considered a valuable immunostain for diagnosing lung adenocarcinoma. DMM are immunonegative with TTF-1. The diagnosis is most straightforward when only DMM or carcinoma markers are positive, but in some cases the staining results are conflicting or ambiguous. In those cases, it is often useful to expand the staining panel to include additional markers. If the result continues to be conflicting, electron microscopy may be considered to assist in accurate diagnosis.
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