Pitfalls in the Diagnosis of Malignant Mesothelioma

37 Pitfalls in the Diagnosis of Malignant Mesothelioma Donald G. Guinee, Jr. and William D. Travis The pathologic assessment of pleural lesions encompasses a variety of neoplastic and reactive conditions that may be difficult to distinguish (Table 37.1). The most common diagnostic problems involve the distinction of an epithelial malignant mesothelioma from adenocarcinoma, and the distinction of reactive epithelial or fibrous proliferations from epithelial or sarcomatoid mesothelioma, respectively. Pleural involvement by benign or malignant processes may sometimes simulate mesothelioma. Likewise, some types of mesotheliomas may simulate either benign processes or other types of malignancies. Integration of histologic, clinical, and radiographic data is important in arriving at an accurate diagnosis. Epithelial Mesothelioma Versus Mesothelial Hyperplasia In some cases, the differential diagnosis between mesothelioma and an organizing pleural effusion with reactive mesothelial hyperplasia may be exceedingly difficult (1 3). The strongest criterion of malignancy is the presence or absence of stromal invasion. Benign mesothelial proliferations associated with organizing pleuritis lack invasion. Glands or cells may become incorporated into the thickened pleura, but these tend to be oriented parallel to the surface. There is often a gradation of cellularity from higher (toward the pleural cavity or subpleural) to lower (or sclerotic) toward the chest wall or lung (Fig. 37.1). Mesothelioma, on the other hand, may either show glands and cells with no particular orientation to the surface (Fig. 37.2A,B) and no particular gradient of cellularity or with increased cellularity toward the chest wall or lung. The presence of mesothelial cells within fat or muscle of the chest wall or within the lung parenchyma is consistent with invasion and strongly supports the interpretation of malignant mesothelioma. True papillary formations deep within tissue are also usually a sign of invasion and consistent with malignancy. Immunohistochemical staining for cytokeratin may be helpful in confirming the presence 555

556 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Table 37.1. Problems in the differential diagnosis of malignant mesothelioma Epithelial mesothelioma vs. mesothelial hyperplasia Organizing pleuritis vs. sarcomatoid or desmoplastic mesothelioma Benign processes or neoplasms mimicking mesothelioma Fibrous pleurisy (chronic fibrous pleuritis) Reactive eosinophilic pleuritis Nodular mesothelial hyperplasia Xanthomatous pleuritis Adenomatoid tumor Thymoma Metastatic or primary malignancies of the pleura mimicking malignant mesothelioma Carcinoma simulating mesothelioma ( pseudomesotheliomatous carcinoma ) Vascular tumors simulating mesothelioma Epithelioid hemangioendothelioma Angiosarcoma Primary pleural synovial sarcoma Metastatic melanoma simulating mesothelioma Primary effusion lymphoma and pyothorax associated lymphoma Mesothelioma simulating other malignancies Localized mesothelioma Desmoplastic mesothelioma simulating sclerosing mediastinitis Mucin-positive mesothelioma Lymphohistiocytoid mesothelioma Deciduoid mesothelioma Mesothelioma of low malignant potential Well-differentiated papillary mesothelioma Diagnostic pitfalls in metastatic mesothelioma Mesothelial cells in mediastinal lymph nodes of invasion into chest wall or in illustrating the pattern of glands within a thickened pleura (Fig. 37.2C). Pathologists should be cautious in the interpretation of invasion as mesothelial cells within fibrinous exudates or tangential sections of pleura with reactive mesothelial cells may simulate invasion. Besides invasion, other features suggesting malignancy include marked cytologic atypia, lack of inflammation, atypical mitoses, and tumor necrosis (Tables 37.2 and 37.3) (2,3). Cytologic atypia should be assesed with caution as reactive mesothelial cells are often atypical in an inflammatory background. Tumor necrosis must also be distinguished from necrotic inflammatory exudates, which may complicate pleural diseases. Nonetheless, a pathologist can render a diagnosis of malignant mesothelioma in the absence of stromal invasion if biopsies from a solid tumor mass show conclusive cytologic features of malignancy. These features are summarized in Tables 37.2 and 37.3. In addition to histologic features, some authors have suggested other ancillary techniques to aid in the distinction of benign from malignant mesothelial proliferations. These efforts have included counting the silver nucleolar organizer regions, and staining for p-glycoprotein, p53, and telomerase reverse transcriptase (3 7). However, the International Mesothelioma Panel has not recommended these techniques for

diagnosis, and additional studies are needed to further establish their utility. When unable to make a definitive diagnosis, the biopsy should be considered an atypical mesothelial proliferation to indicate the uncertainty. Definitive diagnosis may be more difficult in small biopsies. D.G. Guinee, Jr. and W.D. Travis 557 A Figure 37.1. A,B: Organizing pleural effusion. There is a gradation of cellularity from higher (underneath pleural surface) to lower (or sclerotic) toward the chest wall. Mesothelial cells, when entrapped, tend to be arranged parallel to the pleural surface. B

558 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma A B Figure 37.2. Malignant mesothelioma, epithelial type. A,B: A thickened pleura is infiltrated by a haphazard proliferation of irregular glands and cells. C: The presence of mesothelial cells within fat of the chest wall is highlighted by immunohistochemical staining for cytokeratin, consistent with invasion.

D.G. Guinee, Jr. and W.D. Travis 559 C Figure 37.2. Continued Table 37.2. Features favoring malignancy in epithelial mesothelial proliferations True stromal invasion Infiltration of (1) chest wall fat or skeletal muscle or (2) visceral pleural connective tissue or interlobular septa True papillary formations within tissue Irregular orientation of nests of mesothelial cells with respect to pleural surface Marked cytologic atypia Diffusely high cellularity without gradation Atypical mitoses Tumor necrosis Table 37.3. Features favoring reactive mesothelial proliferation associated with an organizing pleural effusion No stromal invasion No infiltration of fat or skeletal muscle of chest wall No true papillary formations within tissue Parallel orientation of nests of mesothelial cells with respect to pleural surface (presumably representing entrapped cells within an organizing pleural effusion) Only mild to moderate nuclear atypia Gradation of cellularity from higher (toward the pleural cavity or subpleural) to lower or sclerotic (toward chest wall or lung) Mitoses confined to cells outside of tissue; no atypical mitoses Absence of tumor necrosis

560 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Organizing Fibrous Pleuritis Versus Sarcomatoid or Desmoplastic Mesothelioma As in the distinction of reactive epithelial mesothelial proliferations from epithelial mesothelioma, the distinction of reactive fibrous pleural proliferations from sarcomatoid mesotheliomas may be difficult. Mesotheliomas in which there is a prominent collagenous stroma, termed desmoplastic mesotheliomas, may be especially problematic as they may contain only scattered cytologically atypical cells within a prominent sclerotic background (8,9). As with epithelial mesothelial proliferations, invasion of the chest wall or visceral pleura strongly supports malignancy (Fig. 37.3). Immunohistochemical staining for cytokeratin is helpful in highlighting infiltration of chest wall fat or skeletal muscle by atypical spindled mesothelial cells. Keratin expression is also useful in highlighting whether the pattern of a spindled cell proliferation is orderly or disorderly (2,9 11). Caution should be used, however, in more superficial areas of the biopsy as subserosal fibroblasts may show keratin expression in reactive conditions (12). Besides invasion, frankly sarcomatous foci, necrosis, pattern of cellularity, and the relative absence of associated inflammation are also helpful in distinguishing desmoplastic mesothelioma from reactive processes. Frankly sarcomatous areas are consistent with malignancy, whereas organizing fibrous pleuritis tends to show a gradient of cellularity ( zonation ) from higher toward the pleural cavity (subpleural), and lower toward the chest wall or the lung. Foci of bland necrosis in a spindled cell proliferation or the presence of distant metastases are also consistent with malignancy. Desmoplastic mesotheliomas typi- Figure 37.3. Malignant mesothelioma, desmoplastic type. Invasion of fat of chest wall by scattered atypical cells of desmoplastic mesothelioma.

Table 37.4. Features favoring malignancy in spindle cell proliferations involving the pleura Invasion of the chest wall Atypical cytokeratin positive cells within fat or skeletal muscle Frankly sarcomatous areas Areas of bland necrosis Distant metastases Storiform pattern D.G. Guinee, Jr. and W.D. Travis 561 cally show a storiform pattern of spindled cells that sometimes form nodules with increased cellularity. In contrast, reactive pleural fibrosis or pleural plaques show a different pattern. Reactive pleural fibrosis often demonstrates a parallel arrangement of blood vessels oriented perpendicular to the pleural surface (2,3,9 11). Pleural plaques show a basket-weave pattern of dense fibrous tissue with slit-like spaces unlike the haphazard or storiform arrangement in desmoplastic mesothelioma. These histologic features are summarized in Tables 37.4 and 37.5. Benign Processes Mimicking Mesothelioma Some types of benign processes, both inflammatory and neoplastic, can mimic mesothelioma histologically. Inflammatory processes that may mimic or enter into the differential diagnosis of mesothelioma include chronic fibrous pleuritis, reactive eosinophilic pleuritis, socalled nodular mesothelial hyperplasia, and pleural inflammation, which contains numerous foamy macrophages ( xanthomatous pleuritis ). Benign neoplasms or neoplasms of indeterminate malignancy that may mimic malignant mesothelioma include adenomatoid tumors and sometimes thymomas. Chronic pleuritis, when severe, may cause marked diffuse pleural fibrosis. This entity, termed fibrous pleurisy or chronic fibrous pleuritis, can mimic mesothelioma radiographically. Histologically, biopsies may show a haphazard growth pattern and focal cytologic atypia of mesothelial cells, especially in the presence of inflammation. Although tongues of fibrous tissue may extend into parietal pleural fat, this extension does not constitute invasion and keratin stains do not demonstrate invasive growth of mesothelial cells (2). Table 37.5. Features favoring reactive organizing pleuritis in spindle cell proliferations involving the pleura No chest wall invasion Gradation of cellularity from high (toward pleural cavity or subpleural) to low (toward chest wall or lung) No areas of necrosis within spindle cell proliferation No distant metastases Absence of a storiform pattern Parallel orientation of blood vessels oriented perpendicular to the pleural surface

562 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma A B Figure 37.4. A,B: Reactive eosinophilic pleuritis. An exuberant inflammatory infiltrate is present along the pleural surface consisting of numerous eosinophils admixed with histiocytes, lymphocytes, and occasional multinucleated giant cells. Reactive eosinophilic pleuritis (Fig. 37.4) is a condition originally described by Askin et al (13), in which there is a pleural inflammatory infiltrate consisting of sheets or nodules containing numerous eosinophils, reactive mesothelial cells, histiocytes, lymphocytes, and occasional giant cells (13,14). This reaction is usually an incidental histologic finding that often follows pneumothorax, and when exuberant, may enter into the histologic differential diagnosis of malignant mesothelioma. Radiographic findings are often of pneumothorax, but diffuse pleural thickening or multiple pleural nodules are not present. Tissue is received in pathology typically after resection of pulmonary blebs or bullae. Histologically, there is no evidence of invasion. If uncertain, immunohistochemical stains for histiocytic markers (CD45 and CD68) will highlight the histiocytic cells and confirm the diagnosis. Nodular mesothelial hyperplasia is a condition first described by Rosai and Dehner (15) in 1975 as a distinct nodular lesion occurring in hernia sacs. The authors attributed the lesions to nodular collections of reactive mesothelial cells and noted their benign nature despite their sometimes worrisome histologic appearance. Chan et al (16) subsequently reported the observation of similar lesions consisting of cellular nodules in two patients in transbronchial biopsies. These lesions occurred in proximity to strips of mesothelium presumably from bits

of visceral pleura sampled by the biopsy. Ordonez et al (17) also reported a similar finding in the pleural biopsies from two patients. Grossly, these are focal nodular lesions usually lacking the diffuse pleural thickening typical of mesothelioma. Histologically, pleural nodular mesothelial hyperplasia is characterized by nodules of cohesive polygonal cells with nuclear grooves. The mononuclear cells may sometimes contain large intracytoplasmic vacuoles (Fig. 37.5). Although initially thought to represent collections of mesothelial cells, positive staining for CD68 in most cells supports a histiocytic reaction (16,17) and can be used to support the diagnosis. Occasional pleural biopsies may show sheets of foamy macrophages that may mimic mesothelioma, metastatic melanoma, or metastatic carcinoma. These findings, which we term xanthomatous pleuritis, typically occur in a background of pleural thickening and fibrosis with variable numbers of admixed lymphocytes, plasma cells, neutrophils, and eosinophils (Fig. 37.6). Clinically, patients may present with pleural effusion(s) or sometimes empyema. Positive immunohistochemical staining for histiocytic markers (CD68) and negative staining for cytokeratin confirms the diagnosis in uncertain cases. Adenomatoid tumors are small tumors often found incidentally during pelvic surgery in the male or female genital tracts (18,19). They are considered a form of benign mesothelioma. Four cases have been D.G. Guinee, Jr. and W.D. Travis 563 Figure 37.5. Nodule of histiocytes along pleural surface. Immunohistochemical staining for CD68 highlights a nodular aggregate of histiocytes along the surface of the pleura. (Courtesy of Dr. David Dail.)

564 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Figure 37.6. Xanthomatous pleuritis. Sheets of foamy macrophages in a background of chronic pleuritis may mimic metastatic carcinoma, metastatic melanoma, or clear cell mesothelioma. reported in the pleura consisting of small nodules ranging from 0.5 to 3.0 cm found incidentally during surgery for lung masses (20 22). Histologically, the tumors consisted of irregularly arranged tubules and glands lined by epithelioid cells. Individual cells were also present, sometimes containing cytoplasmic vacuoles (Fig. 37.7). The tumor cells stain similarly to mesothelial cells. They stain positively for cytokeratin, calretinin, and HBME-1, and negatively for carcinoembryonic Figure 37.7. Adenomatoid tumor. A nodular aggregate of irregularly arranged tubules and glands lined by epithelioid cells.

antigen (CEA), BER-EP4, B72.3, and CD15 by immunohistochemistry (19,22). Ultrastructural examination of one case showed slender microvilli typical of mesothelial cells (22). Although their histologic features overlap somewhat with mesothelioma, the presence of abundant fibrous stroma and a bland appearance of the cells favor adenomatoid tumor. In uncertain cases, adenomatoid tumors are usually readily distinguished from mesotheliomas by their clinical characteristics. Adenomatoid tumors present as a small incidental solitary nodule usually found during another surgery. Malignant mesothelioma, on the other hand, presents with diffuse pleural thickening or multifocal pleural nodules. Thymoma may occasionally present as a pleural tumor (23,24) either primary or as secondary involvement from a mediastinal origin. The diagnosis of primary pleural thymoma requires exclusion of a mediastinal mass. Clinically, these patients may be asymptomatic or present with respiratory difficulty, weight loss, or fever. Chest radiograph may show a localized mass or diffuse pleural thickening with encasement of the lung. Nodular thickening with extension along fissures was noted on one case. While thymomas may resemble mesothelioma clinically, they can usually be distinguished on histologic grounds. Histologically, these lesions are identical to thymomas presenting in the anterior mediastinum and consist of a variable mixture of lymphocytes and epithelial cells, subdivided into lobules by broad fibrous bands (Fig. 37.8). Mesotheliomas, on the other hand, often have an absent or inconspicuous lymphoid component and lack the lobulations characteristic of thymomas. Tubules or papillary formations are not usually found in thymoma, but they are typical of mesothelioma. Immunohistochemical staining for cytokeratin and lymphoid markers (especially CD45 and CD3) highlights the admixed epithelial and lymphoid cells. Available follow-up suggests a variable course with prolonged survival in some patients (24). D.G. Guinee, Jr. and W.D. Travis 565 Metastatic or Primary Malignancies of the Pleura Mimicking Malignant Mesothelioma Metastatic or primary malignant processes may mimic mesothelioma clinically, pathologically, or both. Peripheral lung carcinoma ( pseudomesotheliomatous carcinomas ), indeterminate and malignant vascular neoplasms, primary sarcomas, metastatic melanoma, and primary pleural lymphomas may be confused with mesothelioma. As in the preceding discussion, these entities are distinguished by integration and consideration of clinical, radiographic, and pathologic features. Peripheral lung carcinomas may sometimes diffusely involve the pleural surface in a manner similar to that of mesothelioma (25 27). These patients are typically older men who present with nonspecific respiratory complaints including dyspnea, cough, and chest pain. A minority of patients have previous exposure to asbestos. A unilateral pleural effusion with or without pleural masses is the most common

566 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma A B Figure 37.8. A,B: Thymoma. Lobular aggregates of lymphocytes and epithelial cells similar to mediastinal thymomas. abnormality on chest radiograph. Unlike typical forms of lung cancer, hemoptysis is an uncommon presenting symptom. At thoracotomy, the pleura is often diffusely thickened or has multiple nodules. Histologically, these tumors consist of a mixture of glands, nests, papillary structures, or sheets of malignant cells (Fig. 37.9). Some tumors may have areas of spindled cells. If a portion of lung is included, foci of subpleural adenocarcinoma may be present (25,26). Special stains and immunohistochemistry are helpful in the distinction of pseudomesotheliomatous carcinomas from mesotheliomas.

Unlike mesothelioma, periodic acid-schiff (PAS)-positive, diastaseresistant mucin is present in most pseudomesotheliomatous carcinomas. This mucin resists hyaluronidase pretreatment. Although traditionally recognized as adenocarcinomas, the 1999 World Health Organization (WHO) definition of poorly differentiated adenocarcinoma requiring the presence of at least five mucin-positive cells in two high-power fields would lead to the reclassification of many of these tumors as large-cell carcinomas. Positive immunohistochemical staining for two or more markers recognizing carcinoma such as CEA, CD15, MOC31, BER-EP4, and B72.3 support the diagnosis (25,26,28). Markers of mesotheliomas such as calretinin and cytokeratin (CK) 5/6 are typically negative. Expression of thyroid transcription factor-1 (TTF-1) in pseudomesotheliomatous carcinomas may also be helpful in confirming a pulmonary origin (28 30). The International Mesothelioma Panel and 2003 WHO classification recommend the following workup as a minimum in the distinction of pseudomesotheliomatous carcinoma from mesothelioma: two markers of carcinoma (e.g., CEA and B72.3), two markers of mesothelioma (e.g., calretinin and CK 5/6), a pancytokeratin, TTF-1, and a mucin stain. The prognosis of pseudomesotheliomatous carcinoma is as dismal as that of mesothelioma. Median survival was reported at 8 months. Attempts at radiotherapy and chemotherapy have been largely unsuccessful (26). Vascular neoplasms on occasion may mimic mesothelioma clinically and pathologically (31). Epithelioid hemangioendothelioma or epithelioid angiosarcoma may diffusely involve the pleural, peritoneal, or D.G. Guinee, Jr. and W.D. Travis 567 Figure 37.9. Pseudomesotheliomatous adenocarcinoma. Peripheral lung adenocarcinoma diffusely involving the pleura in a manner similar to mesothelioma.

568 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma pericardial cavities either primarily or secondarily and present with a unilateral pleural effusion or diffuse pleural or peritoneal thickening. Histologically, these tumors are often biphasic consisting of nests of epithelioid cells with varying amounts of a spindle cell stroma. Other features of vascular differentiation are present such as intracytoplasmic vascular lumina (sometimes containing entrapped erythrocytes), and microcystic or vascular spaces lined by tumor cells. A tubulopapillary pattern reminiscent of mesothelioma may be present (Fig. 37.10). Greater nuclear atypia should prompt consideration of epithelioid angiosarcoma (Fig. 37.11). Immunohistochemical stains may help in the distinction of these tumors from malignant mesothelioma and in the confirmation of their vascular origin. In Lin et al s (31) series of 14 patients, immunohistochemical staining for cytokeratin was variable ranging from weak to moderate. Mesotheliomas, on the other hand, are typically strongly positive for cytokeratin. Immunohistochemical staining for factor VIII, CD34, or CD31 help to confirm the interpretation. The prognosis of these tumors is dismal. Most patients die of their disease. Synovial sarcomas are rare tumors that may occasionally present in the pleura and cause confusion with malignant mesothelioma (32 34). Distinction of synovial sarcoma from malignant mesothelioma rests on consideration of clinical, radiographic, and histologic features. Clinically, synovial sarcoma typically occurs in younger patients (average age 25), grows at a faster rate than mesotheliomas, and appears radiographically as a pleural-based mass that is usually localized and only rarely is associated with diffuse pleural thickening. Mesothelioma, on the other hand, typically presents in older patients, grows slowly over years, and presents radiographically as diffuse pleural thickening or Figure 37.10. Epithelioid hemangioendothelioma. Nests of epithelioid cells with occasional cytoplasmic vacuoles. (Courtesy of Dr. David Dail.)

D.G. Guinee, Jr. and W.D. Travis 569 Figure 37.11. Angiosarcoma. Irregular anastomosing cords of malignant cells and associated hemorrhage present within a thickened pleura. (Courtesy of Dr. David Dail.) multiple pleural nodules. Histologically, synovial sarcomas are similar to their counterparts in soft tissue consisting of a biphasic proliferation of epithelioid and spindled areas or as a monophasic proliferation of spindle cells (Fig. 37.12). In contrast to mesothelioma, gland-like spaces often stain positively for mucin by PAS with diastase or mucicarmine. Synovial sarcomas are usually weakly positive for pancytokeratin, CK 7, and epithelial membrane antigen (EMA). In contrast to mesotheliomas, synovial sarcomas may show staining of the glandular component for BER-EP4, but usually lack WT-1 by immunohistochemistry (35). Calretinin expression should be interpreted with caution as most biphasic synovial sarcomas have shown variable expression (35). Electron microscopy also may be useful in difficult cases as features of mesothelioma such as long, thin, slender microvilli are absent in synovial sarcoma (32,33). Finally, fluorescent in situ hybridization may identify the characteristic chromosomal translocation t(x;18) (p11.2;q11.2) and help to confirm the diagnosis (34). Since synovial sarcoma commonly metastasizes to the lung, a thorough search should be performed for an extrathoracic primary before accepting the pleura as the site of origin. We have also seen rare cases of malignant melanoma metastatic to the pleura mistaken for malignant mesothelioma. While there may be overlap in the histologic features of mesothelioma, melanomas are more likely to show cellular pleomorphism, high mitotic rate, and nuclear cytoplasmic inclusions. Cytoplasmic melanin pigment can be highlighted on a Fontana-Masson stain. Negative immunohistochemical staining for cytokeratin and positive staining for melanoma markers

570 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Figure 37.12. Synovial sarcoma. Biphasic proliferation of malignant epithelioid and spindled cells. such as HMB-45, S-100, and tyrosinase are helpful in confirming the diagnosis. Pleural effusion lymphomas and pyothorax-associated lymphomas are types of lymphomas that present in the pleura and enter into the differential diagnosis of malignant mesothelioma. Pleural effusion lymphoma is a recently described entity that occurs as a lymphomatous effusion involving the pleural, pericardial, or peritoneal space in patients with advanced AIDS. They usually do not have a clinically apparent mass throughout their course (36 39). Smears from the pleural fluid show round to ovoid malignant lymphoid cells with large round nuclei. Occasional cells are pleomorphic with multiple nuclei (Fig. 37.13). Mitotic figures are numerous. The neoplastic lymphoid cells lack expression of T- or B-cell antigens on flow cytometry, but do express leukocyte common antigen (CD45) and activation markers [CD30, CD38, human leukocyte antigen (HLA)-DR, and CD71]. The malignant cells consistently show immunoglobulin heavy chain gene rearrangements on Southern blot hybridization. Human herpes virus 8 (HHV8) may be identified in all cases by polymerase chain reaction (PCR) or Southern blot analysis (36,38). In most cases, there is co-infection with Epstein- Barr virus (EBV). Response to chemotherapy in AIDS patients with pleural effusion lymphomas has been poor. Most patients survive only several months. Pleural effusion lymphomas are distinct from pyothorax-associated lymphomas that arise in the setting of long-standing pleural inflammation in mine workers and after artificial pneumothorax or tuberculous pleuritis (40 43). In contrast to pleural effusion lymphomas, pyothorax-associated lymphomas usually have an associated pleural mass, and are associated only with EBV but not HHV8 (44). These are

large B-cell lymphomas, sometimes with a prominent background of T cells. Both pleural effusion lymphomas and pyothorax-associated lymphomas are easily distinguished from mesothelioma by immunohistochemical stains. In contrast to mesotheliomas, both of these tumors lack staining for cytokeratin but express leukocyte common antigen (CD45), confirming their lymphoid origin. D.G. Guinee, Jr. and W.D. Travis 571 A Figure 37.13. Pleural effusion lymphoma. Papanicolaou stained (A) and Wright Giemsa air dried (B) smears of pleural fluid with large malignant lymphoid cells, some containing multiple nuclei. B

572 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Mesotheliomas as Mimickers of Other Diseases Mesotheliomas may simulate either inflammatory conditions or other neoplasms clinically, histologically, or both. Examples of such diagnostic dilemmas include localized mesothelioma mimicking adenocarcinoma, desmoplastic mesothelioma simulating sclerosing mediastinitis, mucin-positive mesothelioma, the distinction of lymphohistiocytoid mesotheliomas from lymphomas, and the distinction of deciduoid mesothelioma from exuberant decidual reactions. As in prior discussions, accurate diagnosis relies on integration of the clinical, radiographic, and histologic findings. Rarely, mesotheliomas may present as a solitary localized pleural mass. This type of presentation may cause confusion as it is much more typical of adenocarcinomas. Patients with these tumors are often asymptomatic when a solitary extrapulmonary mass is discovered on routine chest x-ray. Computed tomography (CT) scan confirms the pleural location and solitary nature of these masses. Grossly, these tumors are sessile or pedunculated ranging up to 10 cm in maximum dimension. Histologically, they are similar to more typical mesotheliomas with epithelial or spindle cell components. Histochemical, immunohistochemical, and ultrastructural findings are also consistent with a mesothelial origin. Unlike the typical presentation of mesothelioma, complete surgical resection may be curative in some cases. Five of six patients in Crotty et al s (45) series had long-term tumor-free survival after surgical excision alone (46). Crotty et al (47) reported a case of desmoplastic mesothelioma that simulated sclerosing mediastinitis. Sclerosing mediastinitis is an exuberant fibroinflammatory reaction within the mediastinum that typically occurs as a late sequela of Histoplasma capsulatum infection. The diagnostic difficulty in this case stems from the unusual presentation of mesothelioma as a localized mass in the mediastinum rather than as diffuse pleural thickening or nodularity. Overlap of histologic findings may also cause confusion as areas of fibrosis are a prominent feature of both desmoplastic mesothelioma and sclerosing mediastinitis. The findings of focal frankly sarcomatous foci allowed the final diagnosis in this case (47). Cytokeratin expression in atypical spindle cells also supported the interpretation of desmoplastic mesothelioma. Although reactive subserosal fibroblasts may express cytokeratin (12), the dense fibrous tissue proliferation deep to the pleural surface in sclerosing mediastinitis should be keratin negative unless entrapped epithelial structures such as thymic epithelium are present. The demonstration of neutral mucin (e.g., by mucicarmine or PAS with diastase) within a malignant epithelial pleural neoplasm has been regarded as proof of adenocarcinoma. However, rare cases of mucinpositive mesothelioma have been reported (48,49). These cases show mucicarmine and PAS-positive, diastase-resistant staining within cytoplasmic vacuoles of malignant cells. This staining is unaffected by pretreatment with hyaluronidase. The cases reported were similar in all other respects pathologically to more typical mesotheliomas. Thus, although rare, neutral mucin may occur in mesotheliomas (48,49).

D.G. Guinee, Jr. and W.D. Travis 573 Figure 37.14. Lymphohistiocytoid mesothelioma. Histiocytoid cells with a prominent chronic inflammatory infiltrate superficially resembling lymphoma. (Courtesy of Dr. Elisabeth Brambilla.) However, in such cases the diagnosis of mesothelioma should be made only if all other morphologic, immunohistochemical, and ultrastructural features are consistent with this interpretation. Electron microscopy may be particularly helpful in supporting the interpretation of mesothelioma in these cases. Lymphohistiocytoid mesothelioma is a rare variant of sarcomatoid mesothelioma that can sometimes be confused with lymphoma. Clinically, patients with these neoplasms present with pleural thickening, effusion, or nodularity similar to other types of mesotheliomas. Histologically they are characterized by variable numbers of ovoid to spindle-shaped mesothelial cells that somewhat resemble histiocytes with a prominent admixed chronic inflammatory infiltrate consisting of lymphocytes and plasma cells (Fig. 37.14). Although superficially resembling lymphoma, they are readily distinguished by positive immunohistochemical staining of the histiocytoid mesothelial cells for cytokeratin. While background lymphocytes consist predominantly of mature T cells (CD45 +, CD3 + ), the mesothelial cells lack staining with lymphoid markers. The mesothelial cells stain positively for cytokeratin and calretinin and stain negatively for other markers typically found in adenocarcinoma such as CEA, BER-EP4, and B72.3 (50,51). Deciduoid mesothelioma is another rare variant of mesothelioma that may be mistaken for florid decidual reactions. Although initially reported in the peritoneum of young women (52), similar tumors have more recently been reported in the pleura in both adult men and women (53,54). Grossly, these tumors present similar to other mesotheliomas as multiple pleural nodules or as a diffuse rind encasing the underlying lung parenchyma. Histologically, they consist of sheets or trabeculae of large polygonal or ovoid cells with large vesicular nuclei

574 Chapter 37 Pitfalls in the Diagnosis of Malignant Mesothelioma Figure 37.15. Deciduoid mesothelioma. Large polygonal cells with abundant cytoplasm, large vesicular nuclei and prominent nucleoli. (Courtesy of Dr. David Dail.) and prominent nucleoli resembling decidua (Fig. 37.15). Deciduoid mesotheliomas may be differentiated from deciduoid reactions by their greater cytologic atypia, greater mitotic activity, and ultrastructural features. While staining for cytokeratin in decidual reactions has been variably reported as absent or focally positive, deciduoid mesotheliomas are consistently diffusely strongly positive for cytokeratin 5/6. These tumors also stain positively for markers of mesothelial differentiation (HBME-1 and calretinin) and negatively for markers expressed by adenocarcinoma (CEA, BER-EP4, and Leu M1) (52 54). Rare Variants of Mesothelioma with Indeterminate Behavior Well-differentiated papillary mesothelioma is a rare variant of mesothelioma originally thought to be restricted to the peritoneum, but more recently reported in the pleura (55,56). This variant is important to distinguish from the more typical diffuse malignant mesothelioma because of its generally better prognosis. Patients often present with dyspnea or recurrent pleural effusions. The effusions may be accompanied by nodular pleural thickening or a solitary mass radiographically. Histologically, the tumors consist of thin fibrovascular papillary cores lined by a single layer of bland cuboidal to flattened mesothelial cells. Mitoses are generally absent and invasion into the underlying pleura is uncommon or focal. The lining cells stain similarly to other mesothelial cells with positive staining for cytokeratin, HBME-1, and calretinin and negative staining for markers of adenocarcinoma (CEA,

B72.3, and Leu M1). Ultrastructural features are similar to those of other mesotheliomas with long slender microvilli. Well-differentiated papillary mesotheliomas may be distinguished from the more typical diffuse malignant mesotheliomas by the diffusely infiltrative nature of the latter. While initial reports of well-differentiated papillary mesothelioma suggested an entirely benign prognosis, more recent studies have suggested a variable course, with resolution in some patients and progression in others. Progression in some patients may be due to the presence of an unsampled or unrecognized diffusely infiltrative component (56). D.G. Guinee, Jr. and W.D. Travis 575 Diagnostic Pitfalls in the Diagnosis of Metastatic Mesothelioma Hyperplastic mesothelial cells may occasionally involve the sinuses of mediastinal or pelvic lymph nodes and cause confusion with metastatic mesothelioma or carcinoma (57 61). This finding usually occurs in the setting of a patient with pleural or pericardial inflammation or effusions. Some affected patients have had constrictive pericarditis or coronary artery disease. Histologically, there are small clusters or single cells within the lymph node sinus. Occasional cases with numerous cells can occur. Rare cases with cells in extranodal sinuses have also been reported (57). Individual cells are bland with eosinophilic cytoplasm and a central nucleus. While these cases can often be distinguished from metastatic carcinoma by immunohistochemical stains, distinction from metastatic mesothelioma may be more difficult and often requires careful clinicopathologic correlation (57 61). References 1. Churg A. Diseases of the pleura. In: Thurlbeck WM, Churg AM, eds. Pathology of the Lung, 2nd ed. New York: Thieme, 1995:1067 1109. 2. Churg A, Colby TV, Cagle P, et al. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol 2000;24:1183 1200. 3. Henderson DW, Shilkin KB, Whitaker D. Reactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ: a brief review. Am J Clin Pathol 1998;110:397 404. 4. Mayall FG, Goddard H, Gibbs AR. P53 immunostaining in the distinction between benign and malignant mesothelial proliferations using formalinfixed paraffin sections. J Pathol 1992;168:377 381. 5. Ayres JG, Crocker JG, Skilbeck NQ. Differentiation of malignant from normal and reactive mesothelioma cells by the argyrophil technique for nucleolar organizer region associated proteins. Thorax 1988;43:366 370. 6. Ramael M, van den Bossche J, Buysse C, et al. Immunoreactivity for P-170 glycoprotein in malignant mesothelioma and in non-neoplastic mesothelium of the pleura using the murine monoclonal antibody JSB-1. J Pathol 1992;167:5 8. 7. Kumaki F, Kawai T, Churg A, et al. Expression of telomerase reverse transcriptase (TERT) in malignant mesotheliomas. Am J Surg Pathol 2002;26: 365 370.

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