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.
Immunohistochemical staining (immunoperoxidase) of PMM. A. AE1/AE3 keratin positive tumor cells in cords and nests with strong cytoplasmic staining in an epithelioid tumor. Note the perinuclear accentuation of the staining. Cells of diffuse PMM infiltrate extrapleural adipose tissue. Photo courtesy of Dr. Lucian Chirieac. B. Extrapleural adipose tissue is infiltrated by AE1/AE3 keratin positive sarcomatoid PMM. The keratin positivity of the bland appearing spindle cells invading fat offers strong support for the diagnosis of sarcomatoid PMM. Photo courtesy of Dr. Lucian Chirieac. C. Calretinin staining of nuclei and cytoplasm is characteristic of an epithelial type PMM. D. CEA fails to stain PMM. This solid epithelial type PMM is highly cellular. CEA staining is found in most cases of adenocarcinoma, and thus is an important differentiating negative stain for PMM. E. WT-1 strongly stains the nuclei of epithelioid PMM tumor cells. F. WT-1 staining of a sarcomatoid PMM supports the diagnosis. Many of the tumor cell nuclei are stained. In addition, cytoplasmic staining of endothelial cells (linear vascular cords) is present and provides a positive internal control. Weak staining of some mesothelioma stromal cells is also apparent. Photo courtesy of Dr. Lucian Chirieac.
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.
Table 115-2Differential Diagnosis: Epithelial PMM (EPMM) ||Download (.pdf) Table 115-2Differential Diagnosis: Epithelial PMM (EPMM)
|Atypical mesothelial proliferation |
Desmoplastic small round cell tumor
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).
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 EPMM3–5 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
Table 115-3Differential Diagnosis: Sarcomatoid PMM ||Download (.pdf) Table 115-3Differential Diagnosis: Sarcomatoid PMM
|Calcifying fibrous tumor |
Metastatic malignant melanoma
Angiosarcoma, Synovial sarcoma, other sarcomas
Pulmonary, Renal cell, other
Solitary fibrous tumor
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