Recognition of Histopathologic Patterns of Diffuse Malignant Mesothelioma in Differential Diagnosis of Pleural Biopsies

Most pathologists recognize that diffuse malignant mesothelioma (DMM) can be divided into 3 basic histologic types—epithelial, biphasic, or sarcomatous.1–6 However, there is a great diversity of histologic patterns within these 3 basic histologic types and some DMM may exhibit multiple histologic patterns.1–7 There are no significant clinical differences among these histologic patterns of DMM, and, therefore, differentiation of these patterns from each other is usually not crucial from a clinical or a treatment perspective.7 However, it is important for the pathologist to be aware of these patterns to make a histologic differentiation between DMM and other neoplasms.8 Much of the literature on the histologic differential diagnosis of DMM, including many investigations of immunohistochemical markers, emphasizes distinction of epithelial DMM from acinar adenocarcinomas of the lung; however, the diverse histologic patterns of DMM potentially include a wider range of histologic differential diagnoses. If unaware of these assorted histologic patterns, the pathologist may not consider DMM as a possible diagnosis in some pleural specimens.

Clinical history, radiologic findings, gross surgical description, and ancillary studies, including histochemistry, immunohistochemistry, electron microscopy, and molecular studies, all have a potential role in differentiating DMM from other neoplasms. It is beyond the scope of this article to discuss the use of immunohistochemistry or other ancillary studies to differentiate the histologic patterns of DMM from other neoplasms. However, it should be remembered that immunoreactivity that differentiates certain patterns of epithelial DMM from adenocarcinoma of the lung may not be applicable to differential diagnoses of other histologic patterns. In this review, the diverse histologic patterns of DMM that pathologists should be conscious of on hematoxylin-eosin–stained sections of pleural biopsies are briefly described; including those infrequently encountered patterns that generate uncommon differential diagnoses.

Epithelial DMM are the most commonly diagnosed histologic type of DMM.3,6 There are several histologic patterns of epithelial DMM and the common patterns are well recognized by most pathologists.7,9 The most commonly occurring patterns include tubulopapillary, adenomatoid (also termed microglandular), and sheetlike patterns composed of well-differentiated cells that cytologically resemble mesothelial cells.3,6 Less commonly occurring epithelial patterns include clear cell, deciduoid, and small cell patterns.3,6 More well-differentiated epithelial DMM may produce an abundance of hyaluronic acid, with clusters or strips of well-differentiated epithelioid tumor cells floating in pools of hyaluronic acid (Figure 1).4 

The tubulopapillary pattern is one of the most common histologic patterns of epithelial DMM6 and is one of the classic patterns that must be differentiated from adenocarcinoma metastatic to the pleura. The tubulopapillary pattern consists of a mixture of small tubules and papillary structures with fibrovascular cores, often with clefts and trabeculae lined by bland and relatively uniform flat, cuboidal, or polygonal cells (Figure 2).3,6 

In the adenomatoid pattern, bland flat to cuboidal cells line small glandlike structures.4 The adenomatoid pattern is often identified with other patterns in a DMM, but may predominate.3,6 The primary differential diagnosis is metastatic adenocarcinoma (Figure 3).

The solid well-differentiated pattern is one of the most common histologic patterns of DMM. The neoplastic cells occur in nests, cords, or sheets and closely resemble nonneoplastic reactive mesothelial cells; that is, round cells with abundant cytoplasm and round, vesicular nuclei with prominent nucleoli. Mitoses are usually not prominent. The most important differential for this pattern is often not other cancers, but, rather, benign reactive mesothelial hyperplasia (Figure 4).

The solid poorly differentiated pattern consists of relatively discohesive polygonal to round tumor cells, with uniform nuclei, arranged predominantly in monotonous sheets.3,4,6 The differential diagnosis includes lymphoma and large cell carcinoma (Figure 5).3 

The acinar pattern of DMM is characterized by acinar or glandlike structures making up the vast majority of the tumor.4 The lumens may be elongate or branching and are generally lined by relatively uniform and relatively bland cuboidal cells. The primary differential diagnosis for this relatively common pattern is metastatic adenocarcinoma (Figure 6).

Clear cell pattern is a rare histologic pattern of DMM characterized by tumor cells with clear cytoplasm.4,10,11 It must be differentiated from other clear cell neoplasms that are metastatic to the pleura, such as renal cell carcinoma, clear cell carcinomas of the lung, clear cell melanoma and others.11,12 The entire DMM may not be clear cell, and the presence of other histologic patterns of DMM may assist in making the correct diagnosis. However, even in DMM with mixed histologic patterns, it is possible that only a clear cell pattern will be sampled on biopsy (Figure 7). Immunoreactivity with mesothelial markers assists in the diagnosis of clear cell DMM.11 

First identified as a peritoneal tumor of poor prognosis arising in girls and young women, the deciduoid pattern of DMM has been identified in the pleura of older men and women and is currently considered to have no independent prognostic significance.13–15 The pattern generally occurs as a focal component along with another predominant histologic pattern of epithelial DMM, but the deciduoid pattern may rarely predominate or be the only area sampled on a biopsy.14 The pattern is characterized by a proliferation of large, round to polygonal cells with sharp cell borders, abundant glassy eosinophilic cytoplasm, and round vesicular nuclei with prominent nucleoli, reminiscent of an exuberant decidual reaction.16–18 Typically, mitotic figures are infrequent.18 Differential diagnosis includes squamous cell carcinoma, gastrointestinal autonomic nerve tumor, pseudotumoral deciduosis, anaplastic large cell lymphoma, oxyphilic variant of ovarian clear cell carcinoma, and trophoblastic neoplasia (Figure 8).16,19,20 Mesothelial markers, such as cytokeratin 5/6 and thrombomodulin, may be positive in metastatic squamous cell carcinoma and would not differentiate this cancer from deciduoid DMM.

Rarely, an adenoid cystic pattern occurs as the predominant histologic pattern in an epithelial DMM.6 Cribriform and tubular growth patterns are separated by a fibrous stroma, containing variable numbers of chronic inflammatory cells. The differential diagnosis includes metastatic adenoid cystic carcinoma and metastatic adenocarcinoma (Figure 9).

Rare cases of DMM may have a signet ring pattern.6,21 Tumor cells lie in clusters or sheets and contain cytoplasmic vacuoles. Signet ring cell adenocarcinoma metastatic to the pleura must be excluded (Figure 10).6 

The small cell pattern of epithelial DMM is extremely rare. Tumor cells are uniform small, round cells with bland nuclei and a high nuclear-cytoplasmic ratio.6,7 These should be differentiated from other small cell neoplasms that may be primary or metastatic to the pleura; including metastatic small cell carcinoma, desmoplastic small round cell tumor, primitive neuroectodermal tumor, and lymphoma. Unlike the typical immunoreactivity pattern found in small cell neuroendocrine neoplasms, small cell DMM tumor cells are immunohistochemically negative for neuroendocrine markers such as CD56, chromogranin, and synaptophysin.22 

Sarcomatous DMM are characterized by spindle cells arranged in fascicles or sheets, resembling fibrosarcoma (Figure 11).3,7 Sarcomatous DMM typically have more mitotic figures, necrosis, and cytologic atypia than epithelial DMM.4 Some sarcomatous DMM contain anaplastic cells and giant cells reminiscent of malignant fibrous histiocytoma.3 Rarely, sarcomatous DMM contain areas of osteosarcomatous or chondrosarcomatous metaplasia,3,6,23–25 and osteosarcoma and chondrosarcoma metastatic to the pleura must be excluded.

The lymphohistiocytoid pattern is characterized by discohesive, atypical histiocytoid-appearing, malignant mesothelial cells within an intense lymphoplasmacytic infiltrate.7 The histiocytoid-like mesothelial tumor cells within the inflammatory infiltrate may easily be overlooked, potentially leading to an incorrect diagnosis of a nonneoplastic inflammatory process. Lymphohistiocytoid pattern DMM must be differentiated from non-Hodgkin lymphoma3 and Hodgkin lymphoma.26 Cytokeratin expression in the lymphohistiocytoid DMM tumor cells assists in excluding other neoplasms in the differential diagnosis.26 

Desmoplastic DMM generally are sarcomatous DMM (although epithelial variants occur) that have extensive dense collagen arranged in a storiform or “patternless” pattern, making up more than 50% of the tumor (Figure 12).3,4,6 This pattern is identified in approximately 5% to 10% of DMM.7 Scant bland tumor spindle cells are interspersed between bands of collagenous stroma that resemble pleural plaque.3,4,7 Foci of frankly sarcomatous DMM may be present, but are not always sampled in small biopsies. Desmoplastic DMM must be differentiated from fibrous pleuritis, and the 2 entities may coexist.7 

Biphasic DMM are characterized by a mixture of epithelial and sarcomatous patterns3,4,6,7 and make up approximately 30% of DMM.3 To meet the criteria for a biphasic or mixed DMM, each histologic type must make up at least 10% of the neoplasm (Figure 13).3,4 Other neoplasms that are primary or metastatic to the pleura that may have biphasic or mixed patterns include carcinosarcomas, biphasic pulmonary blastoma, and biphasic synovial sarcoma.

Pleomorphic pattern refers to DMM, both epithelial and sarcomatous, that have prominent tumor giant cells or anaplastic cells (Figures 14 and 15).3 Pleomorphic DMM must be differentiated from pleomorphic carcinoma and other high-grade, poorly differentiated neoplasms metastatic to the pleura.14 Immunoreactivity for calretinin and TTF-1 are helpful in differentiating pleomorphic DMM from metastatic pulmonary pleomorphic carcinoma.14 

Transitional pattern DMM are characterized by individual tumor cells with a “transitional” appearance, blending both epithelial and sarcomatous features in the same cell (Figure 16).4 

Although there are reports that well-differentiated epithelial DMM are the most likely pattern to benefit from extrapleural pneumonectomy, and that sarcomatous (particularly desmoplastic) DMM have the most aggressive behavior, currently the prognosis of all DMM is poor and therapeutic options are limited. Although the diverse histologic patterns of DMM have no clinical significance in terms of ultimate prognosis and therapy, these patterns do provide a wide differential diagnosis for the pathologist to consider on pleural biopsies.