36
Diagnosis of Synovial Sarcoma
of the Pleura and Differentiation
from Malignant Mesothelioma
Amy Powers and Michele Carbone
Synovial sarcomas (SSs) are soft tissue tumors that occur primarily in
adolescents and young adults between the ages of 15 and 40 (1). The
tumors comprise 5% to 10% of all soft tissue sarcomas, and most commonly arise in extremities in the vicinity of large joints. Rare cases have
also been reported in virtually every anatomic site, including the head
and neck, lung, heart, mediastinum, abdominal wall, central nervous
system (CNS), prostate, and pleura. Synovial sarcomas do not arise
from synovium, as the name implies. Instead, they are thought to arise
from primitive mesenchymal cells, which explains their development
in locations devoid of synovium (1).
Synovial sarcomas of the pleura usually represent metastatic disease,
but more than 20 primary SSs of the pleura have been reported in the
English-language literature, making these tumors a rare but important
diagnostic consideration (Table 36.1) (2–10). The origin of pleural synovial sarcomas may be undifferentiated submesothelial mesenchyme,
which could undergo differentiation toward epithelial or spindle cells.
The rarity of primary synovial sarcoma of the pleura and its morphologic similarity to malignant mesothelioma (MM), the most common
primary malignant pleural lesion, make it a difficult and easily overlooked diagnosis. This chapter discusses the differences between the
two entities.
Clinical History
Clinical features can be useful in distinguishing between MM and SS
of the pleura. However, because there is considerable overlap between
these two entities, clinical findings alone are not always reliable in
making a diagnosis of SS versus MM.
Synovial sarcomas have no significant gender predilection, while
mesotheliomas are more common in males (1). Synovial sarcomas also
tend to occur in younger patients. Of 23 primary SSs of the pleura reported in the literature, the average age was 37 (range 9–77). Mesothe543
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Chapter 36 Synovial Sarcoma of the Pleura
Table 36.1. Primary pleural synovial sarcomas: clinical and pathological features
Author (reference)
Jawahar et al (3)
Gaertner et al (4)
Aubry et al (2)
Nicholson et al (5)
Carbone et al (10)
Colwell et al (6)
Essary et al (7)
Hirano et al (9)
Ng et al (11)
Chan et al (8)
Patient age
18
17
17
50
9
32
33
41
41
49
69
42
28
42
74
39
23
33
30
32
46
15
77
Sex
F
F
F
M
M
F
M
M
M
F
M
M
M
M
M
M
F
M
M
F
F
M
F
Histopathology
Biphasic
Biphasic
Biphasic
Biphasic
Biphasic
Biphasic
Monophasic
Monophasic
Monophasic
Monophasic
Monophasic
Biphasic
Monophasic
Monophasic
Biphasic
Monophasic
Monophasic
Biphasic
Monophasic
Monophasic
Biphasic
Monophasic
Not Stated
Molecular studies
t(X;18)
NP
NP
NP
NP
NP
t(X;18)
t(X;18)
t(X;18)
t(X;18)
t(X;18)
NP
NP
NP
t(X;18)
Negative
t(X;18)
Indeterminant
NP
NP
NP
t(X;18)
NP
NP, not performed.
liomas, in contrast, typically develop in patients 50 to 70 years of age
and are rarely seen in adolescents and young adults. Occasional primary pleural SSs have been reported in older adults, however. Aubry
et al (2) reported a monophasic SS in a 69-year-old man, and Carbone
et al (10) detailed the development of a biphasic SS in a 74-year-old
man. A primary pleural SS in an old individual was also reported by
Chan et al (8), but the histologic subtype was not specified. Thus, a
diagnosis of SS should not be ruled out based on old age alone. Chan
et al suggested that SSs in older individuals (>60 years of age) are more
likely to have unusual histologic patterns and poorly differentiated
morphology, which can make diagnosis more challenging. In addition,
these higher grade lesions are typically associated with aggressive
behavior and frequent metastasis.
Synovial sarcomas typically grow at a faster rate and present radiologically as a discrete, localized mass with or without associated pleural
thickening. A pseudocapsule is occasionally present (4). In contrast,
MMs grow slowly, more commonly present as diffuse pleural thickening or multiple pleural nodules, and do not have capsules or pseudocapsules. Localized MMs are extremely rare, and the presence of a
localized pleural-based mass should instead raise suspicion of a soft
tissue tumor. Pleural effusions, although more common in MM, have
been reported in both malignancies and do not reliably rule out SS (4).
A. Powers and M. Carbone
A clinical history of asbestos exposure in an individual with a
pleural-based tumor should raise the suspicion of an MM. However,
pleural SSs have also been reported to occur in asbestos-exposed individuals, and one should be cautious not to jump to a diagnosis of MM
based on history alone (10).
Gross Pathology
A thorough macroscopic examination must be performed when differentiating between these malignancies, as they tend to have distinct
gross morphologies. Gross examination of 22 reported cases of pleural
synovial sarcoma demonstrated both solid and cystic masses ranging
in size from 4.5 to 25 cm (2–7,9–11). Occasionally, pleural SSs have been
reported to encase a lobe (2) or even an entire hemithorax (10), but they
typically form localized, pleural-based masses with or without pedicles. In rare cases of SS, multifocal patterns have also been reported (6).
Synovial sarcomas tend to be gray-white and fleshy, and frequently
have associated hemorrhage, necrosis, and calcification. Pseudocapsulation was reported in several tumors. These tumors may have associated pleural thickening, and one tumor was associated with pleural
plaques (10).
Malignant mesotheliomas, in contrast, typically present as multiple
nodules covering the pleura or as a diffuse sheet-like pleural thickening that can encase and compress the lungs (1). The tumor may extend
superficially into the lungs, or along needle biopsy tracts. Localized,
solitary discrete masses, in contrast to SS, are extremely rare. The
appearance of MM is also typically gray-white, and can vary from firm
and rubbery to soft and gelatinous. There may be foci of hemorrhage
and necrosis, and this tumor is typically associated with pleural
plaques due to its strong association with asbestos exposure (1).
Histopathology
Malignant mesotheliomas of the pleura typically have an epithelioid,
biphasic, or sarcomatoid pattern. Synovial sarcomas, like MMs, also
exhibit biphasic or sarcomatoid morphology. Theoretically, a monophasic epithelial SS should exist, but this variant could be reliably diagnosed only by using cytogenetic data (1). Since no monophasic
epithelial SS of the pleura have been reported, only the biphasic and
sarcomatoid variants of these tumors are considered in this discussion.
Histologically, biphasic SS and biphasic MM exhibit subtle differences (4,12). Biphasic SS (Fig. 36.1) have a long interweaving spindled
component that is compact and cellular, with little stromal collagen.
Foci of hemiangiopericytomatous architecture (Figs. 36.1A and 36.2)
and of microcalcification (Fig. 36.1D) are characteristic, and hyaline
fibrosis can be present. Mast cells are often prominent, but glycogen is
sparse. In contrast, the spindled component of biphasic MM consists
of shorter, looser fascicles of blunt spindle cells with more stromal collagen. Hyaline fibrosis and hemangiopericytomatous architecture are
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Chapter 36 Synovial Sarcoma of the Pleura
Figure 36.1. Histology of synovial sarcoma (SS). A: Hemgiopericytomatous appearance (100¥).
B: Sarcomatoid SS. C: Biphasic SS, focus of epithelioid differentiation. D: Sarcomatoid SS, focus of
microcalcification.
Figure 36.2. Histology of SS. Hemangiopericytomatous appearance at high
magnification (400¥).
A. Powers and M. Carbone
Figure 36.3. Desmoplastic mesothelioma. Compare with histology of sarcomatoid SS shown in Figure 36.1.
rare. Mast cells are also fewer in number, but glycogen is abundant
(4,12). The epithelial component of biphasic SS typically consists of
epithelial cells forming cleft-like glandular spaces and tubulopapillary
structures. The epithelial component of well-differentiated biphasic
mesotheliomas can also be tubulopapillary, but there is typically a
gradual transition between the sarcomatous and epithelial elements in
these tumors, while there is a sharp abutment of these areas in SS (1).
Sarcomatoid MMs, similar to the spindle component in biphasic
variants, usually consist of short blunt fascicles of pleomorphic tumor
cells (Fig. 36.3). The fascicles may be poorly formed, and cells can have
abundant eosinophilic cytoplasm. Sarcomatoid MM rarely displays a
fibrosarcomatous or hemangipericytomatous pattern. This is distinct
from monophasic SSs, which are composed of longer interweaving fascicles of densely packed, mildly pleomorphic, and overlapping spindle
cells with a high mitotic rate. Moreover, abundant dense collagen deposition among sparse sarcomatoid and/or gland-like epithelioid structures, characteristic of desmoplastic mesothelioma (Fig. 36.3), is not seen
in SS. Monophasic SSs may exhibit a fibrosarcomatous or hemangiopericytomatous pattern, and the presence of either of these two patterns in a
pleural-based lesion should immediately raise suspicion for SS (1,12).
Mucin
Mucin staining is typically not performed in the differentiation between pleural SS and MM, but some authors have observed useful differences in staining. In contrast to MM, pleural SSs contain secretions
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Chapter 36 Synovial Sarcoma of the Pleura
that are mucicarmine positive and hyaluronidase resistant, and periodic acid-Schiff (PAS) positive and diastase resistant. Rare MM may
exhibit mucicarmine or PAS staining, but it is eliminated with
hyaluronidase or diastase digestion (4,12).
Immunohistochemistry
Immunohistochemistry (IHC) plays a limited role in the distinction of
SS from MM, since there are presently no immune markers that are
unique for either entity. We recommend that a panel of markers be used
to support a diagnosis of either of these tumors, which should include
cytokeratins, calretinin, WT-1, Bcl-2, CD56, and CD99.
Both SS and MM display immunoreactivity for vimentin and pancytokeratin. The former, although nonspecific is useful to verify the
immunoreactivity of the tissue (i.e., almost everything stains for
vimentin, Fig. 36.4A). It is our experience and that of others that nearly
100% of MMs are diffusely positive for cytokeratin (10,13); >90% of SSs
(Fig. 36.4B) also display focal reactivity, which is most pronounced in
the epithelioid component (1). While poorly differentiated SSs are less
likely to exhibit cytokeratin positivity, as many as 50% have been
Figure 36.4. Immunoreactivity of SS. A: Vimentin, positive (200¥). B: Cytokeratin 5/6. Note positivity
of superficial and entrapped reactive mesothelial cells. Tumor cells are mostly negative (100¥). C1:
CD99, positive (400¥). C2: Bcl-2, focally positive on spindle tumor cells (200¥). D1: WT-1, negative
(200¥). D2: WT-1, fibrous MM positive control (200¥).
A. Powers and M. Carbone
shown to express focal keratin positivity (14). Thus, it appears that
while the value of cytokeratin alone is limited in differentiating between these two tumors, focal positivity, rather than diffuse staining,
is suggestive of SS.
Like the cytokeratins, the use of calretinin to differentiate between
these two tumors is limited. It is well established that both epithelioid
and sarcomatoid MM express calretinin. Aubry et al (2) observed calretinin reactivity in 44 of 44 mesotheliomas (36 epithelial, five biphasic, and four sarcomatoid). In biphasic mesotheliomas, staining was
seen in both the epithelial (3–4+) and spindle cells (2+). Like MM, SS
can also express this marker. Miettinen et al (15) demonstrated calretinin positivity in 71% of biphasic SS, 52% of monophasic SS, and 56%
of poorly differentiated SS.
While both SS and MM express calretinin, it has been suggested that
this marker may be of some value in differentiating between biphasic
variants of these tumors. Cappello and Barnos (12) observed calretinin
reactivity (2–3+) in the epithelial component of four of four biphasic
MMs. The spindled component was negative in four of four MMs. In
contrast, they observed staining (1–2+) in the spindled component in
four of four biphasic SSs, while the epithelial component was weakly
positive (1+) in only one of four. Thus, they concluded that strong diffuse calretinin staining in the epithelial component of a biphasic tumor
with or without staining of the spindle cells is more indicative of an
MM than an SS.
In contrast to cytokeratin and calretinin, WT-1 appears to be a more
useful marker in differentiating between SS and MM (Fig. 36.4D1,2).
Miettinen et al (15) found that none of 18 biphasic SSs, none of 31
monophasic SSs, and none of 11 poorly differentiated SSs expressed
WT-1. In contrast, 12 of 17 epithelioid MMs expressed WT-1. Similarly,
Amin et al (16) found that 95% of MMs expressed WT-1, including sarcomatous variants. Thus, WT-1 reactivity supports a diagnosis of MM
rather than SS.
Like WT-1, Bcl-2, a protein involved in apoptosis, appears useful in
discriminating between MM and SS of the pleura. Bcl-2 staining was
found in the spindle component of 79% to 100% of SSs (Fig. 36.4C2)
but only in 0 to 10% of MMs (12). In a direct comparision, Cappello
and Barnes (12) observed Bcl-2 reactivity (3+) in the spindle component
of four of four biphasic SSs, but only weak positivity (1–2+) in four of
four biphasic MMs. The epithelial component of two of four SSs and
four of four MMs was also positive (1–2+). Cappello and Barnes suggested that strong spindle cell Bcl-2 staining is more indicative of SS.
The use of Ber-Ep4 is controversial. Reports of Ber-Ep4 staining in
MM are variable. Gaffey et al (17) studied 49 MMs, including epithelioid and biphasic variants, and found that 10 (20%) exhibited focal
(<25%) epithelioid staining. In contrast, Sheibani et al (18) found that
of 115 MMs (including epithelioid, biphasic, and sarcomatoid variants),
only one (0.9%) biphasic tumor stained with Ber-Ep4. Cappello and
Barnes (12) found that four of four biphasic MMs were negative for
Ber-Ep4, while two of four biphasic SSs displayed focal positivity in
the epithelioid component. In the study by Gaetner et al (4), five of five
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Chapter 36 Synovial Sarcoma of the Pleura
pleural-based biphasic SSs exhibited epithelioid staining with Ber-Ep4,
while four of five showed staining in the spindle cell component.
HBME-1 is of limited value in the distinction between SS and MM,
as HBME-1 positivity is seen in epithelioid components of MM as well
as biphasic and monophasic SS (15). Staining for epithelial membrane
antigen (EMA) may also be seen in both, and occasional S-100 positivity is also seen in SS and MM (4). CD99 (Fig. 36.4C1), the product of
the MIC2 gene, has been observed at similar frequencies in both SS and
MM (5). CD56 staining is frequent in SS (1). Both SS and MM typically
demonstrate no reactivity with B72.3, LeuM1, or CD34.
Overall, the use of immunohistochemistry in the distinction between
MM and SS of the pleura is challenging and limited at best. Panels
of markers are recommended since no single marker is diagnostic of
either MM or SS. However, coexpression of Bcl-2, CD56, and CD99 with
negative staining for calretinin, WT-1, and focal cytokeratin positivity
strongly suggests the diagnosis of SS rather than MM.
Electron Microscopy
Ultrastructurally, MMs are characterized by several unique features
that can be useful when trying to differentiate these tumors from SSs.
Classically, biphasic and epithelioid MMs are characterized by long,
slender, tortuous branching microvilli (Fig. 36.5A), but this finding may
be diminished or lost in poorly differentiated neoplasms. Abundant
intracytoplasmic glycogen is also seen. SSs, in contrast, have shorter
blunt microvilli (Fig. 36.5B), and glycogen is sparse to absent (1,9,10).
Molecular Studies
Overall, while clinical history, gross and microscopic examination,
and IHC may suggest a diagnosis of pleural SS, molecular diagnostic
studies are considered the only definite way to differentiate SS from
MM of the pleura. Regardless of histologic subtype, the chromosomal
translocation t(X;18)(p11.2;q11.2) is characteristic of synovial sarcomas
(10). A variety of techniques have been used to detect this translocation
including conventional and molecular cytogenetics and reverse-transcription polymerase chain reaction (RT-PCR). While this translocation
has been occasionally reported in other tumor types, particularly
fibrosarcomas and malignant fibrous histiocytomas, these cases more
likely represent misdiagnosed SS (1).
The characteristic translocation results in fusion of the SYT gene
on chromosome 18 to the SSX gene on chromosome X (Fig. 36.6). This
translocation has been convincingly demonstrated in primary pleural
SSs. Aubry et al (2), using RT-PCR, confirmed the presence of this
translocation in five of five sarcomatoid primary SSs of the pleura.
Carbone et al (10) and Ng et al (11) also confirmed the presence of this
translocation in biphasic and monophasic pleural SSs, respectively.
Overall, of 11 cases of primary pleural SS, nine (82%) contained the
A. Powers and M. Carbone
A
B
Figure 36.5. Electron microscopy characteristics of mesothelioma (A) characterized by long branching microvilli (12,000¥) and of SS (B) showing short blunt
microvilli (8,000¥).
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Chapter 36 Synovial Sarcoma of the Pleura
Figure 36.6. X;18 translocation. A: The different possible molecular rearrangements described in this type of translocation. The translocation detected in this
particular tumor involves the SYT gene on chromosome 18, and the SSX2 gene
on chromosome X. B: Southern blot hybridization showing the X:18 translocation detected in this tumor. Lane 1: Patient RNA extraction purified on Qiagen
column. Lane 3: RNA extraction not purified; (10 ml). Lane 5: RNA extraction
not purified (2 ml). Lane 7: SS-positive control (courtesy of Dr. Lasota). Lanes 9,
11, 13: Negative controls. Lane 14: Molecular weight. Lanes 15 and 19: SSpositive controls from our collection of SS. Lane 17: MM negative control.
Lanes 2, 4, 6, 8, 10, 12, 16, and 18 are empty. RT-PCR.
translocation, one (9%) did not, and one (9%)was indeterminant. While
MM can harbor multiple cytogenetic abnormalities, including partial
loss of chromosome 1 (1p11–p22), chromosome 3 (3p14–p25), and chromosome 9 (9p), there have been no reports of the X;18 translocation
in MM (1,10). Thus, molecular diagnostics is currently an extremely
valuable tool in the differential diagnosis of a pleural-based mass when
there is suspicion of SS.
The type of SYT-SSX fusion gene detected in SS appears to correlate
with both tumor morphology and prognosis. Kawai et al (19) observed
that biphasic morphology correlated with the SYT-SSX2 fusion transcript, and monophasic morphology correlated with the SYT-SSX1
fusion transcript. Furthermore, those patients with biphasic tumors
expressing the SYT-SSX2 fusion transcript had a better survival rate
than those with SYT-SSX1 monophasic SS. Nilsson et al (20) also found
that SS containing the SYT-SSX1 fusion transcripts had poorer
outcomes.
A. Powers and M. Carbone
Conclusion
The true incidence of primary SS of the pleura is unknown. Although
it is a rare tumor, it is likely underdiagnosed and frequently mistaken
for MM, the most common malignant pleural lesion. Diagnosis of
pleural SS can be extremely challenging. The apparent rarity of the
tumor in this location makes it an easily overlooked diagnosis. In
addition, this tumor can be reliably distinguished from a MM only
by using cytogenetics, since these entities have overlapping clinical,
gross, histologic, and immunohistochemical features. This diagnostic
problem has been compounded by the fact that the molecular tools
to diagnose the unique X;18 translocation have only recently become
available. Furthermore, few laboratories have the resources in place to
identify this translocation (4,10,12,15).
While challenging, the distinction between MM and SS of the pleura
is essential, since these entities have distinct treatments and prognosis.
Synovial sarcomas can be responsive to chemotherapy, particularly
to ifosfamide-based regimens, while sarcomatoid mesotheliomas are
chemoresistant (1,21). As a result, synovial sarcomas are treated aggressively, while patients with sarcomatoid mesotheliomas are often given
supportive therapy only. Furthermore, patients with MM have an average survival of less than 12 months, while patients with SS can have
longer survival rates. In a series of primary biphasic SS of the pleura
(4), patients survived an average of 35 months, with a range of 12 to
more than 96 months. With chemotherapy, some authors have reported
5-year survivals as high as 57% in patients with SS (6). Finally, a diagnosis of MM often has important legal consequences, due to its strong
association with asbestos exposure; SS has not been associated with
asbestos, and when mistaken for a MM, it can result in unnecessary
legal fees and settlements.
References
1. Weiss SW, Goldblum JR, eds. Soft Tissue Tumors, 4th ed. St. Louis: Mosby,
2001.
2. Aubry MC, Bridge JA, Wickert R, Tazelaar HD. Primary monophasic
synovial sarcoma of the pleura. Am J Surg Pathol 2001;25:776–781.
3. Jawahar DA, Vuletin JC, Gorecki P, Persechino F, Macera M, Magazeh P.
Primary biphasic synovial sarcoma of the pleura. Respir Med 1997;91:
568–570.
4. Gaertner E, Zeren H, Fleming M, Colby T, Travis W. Biphasic synovial sarcomas arising in the pleural cavity. A clinicopathologic study of five cases.
Am J Surg Pathol 1996;20:36–45.
5. Nicholson AG, Goldstraw P, Fisher C. Synovial sarcoma of the pleura and
its differentiation from other primary pleural tumors: a clinicopathological
and immunohistochemical review of three cases. Histopathology 1998;33:
508–513.
6. Colwell AS, D Cunta J, Vargas S, et al. Synovial sarcoma of the pleura: a
clinical and pathologic study of three cases. J Thorac Cardiovasc Surg 2002;
124:828–832.
553
554
Chapter 36 Synovial Sarcoma of the Pleura
7. Essary LR, Vargas SO, Fletcher CD. Primary pleuropulmonary synovial
sarcoma: reappraisal of a recently described anatomic subset. Cancer
2002;94:459–469.
8. Chan JA, McMenamin ME, Fletcher CDM. Synovial sarcoma in older
patients: clinicopathological analysis of 32 cases with emphasis on unusual
histological features. Histopathology 2003;43:72–83.
9. Hirano H, Kizaki T, Sashikata T, et al. Synovial sarcoma arising from
the pleura: a case report with ultrastructural and immunohistochemical
studies. Med Electron Microsc 2002;35:102–108.
10. Carbone M, Rizzo P, Powers A, et al. Molecular analyses, morphology and
immunohistochemistry together differentiate pleural synovial sarcomas
from mesotheliomas: clinical implications. Anticancer Res 2002;22:3443–
3448.
11. Ng SB, Ahmed Q, Tien SL, et al. Primary pleural synovial sarcoma. A case
report and review of the literature. Arch Pathol Lab Med 2003;127:85–90.
12. Cappello F, Barnes L. Synovial sarcoma and malignant mesothelioma of
the pleura: review, differential diagnosis and possible role of apoptosis.
Pathology 2001;33:142–148.
13. Battifora H, McCaughey WTE. Atlas of Tumor Pathology. Tumors of the
Serous Membrane. Washington, DC: Armed Forces Institute of Pathology,
1995:17–89.
14. Folpe AL, Schmidt RA, Chapman D, Gown AM. Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high grade malignant peripheral nerve sheath
tumors. Am J Surg Pathol 1998;22:673–682.
15. Miettinen M, Limon J, Niezabitowski A, Lasota J. Calretinin and other
mesothelioma markers in synovial sarcoma. Am J Surg Pathol 2001;25:610–
617.
16. Amin KM, Litzky LA, Smythe WR, et al. Wilms’ tumor 1 susceptibility
(WT1) gene products are selectively expressed in malignant mesothelioma.
Am J Pathol 1995;146:344–356.
17. Gaffey MJ, Milles SE, Swanson PE, et al. Immunoreactivity for Ber-Ep4 in
adenocarcinomas, adenomatoid tumors, and malignant mesotheliomas.
Am J Surg Pathol 1992;18:593–599.
18. Sheibani K, Shin SS, Kezirian J, et al. Ber-Ep4 antibody as a discriminant
in the differential diagnosis of malignant mesothelioma versus adenocarcinoma. Am J Surg Pathol 1991;15:779–784.
19. Kawai A, Woodruff J, Healey JH, et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med
1998;228:153–160.
20. Nilsson G, Skytting B, Xie Y, et al. The SYT-SSX1 variant of synovial
sarcoma is associated with a high rate of tumor cell proliferation and poor
clinical outcome. Cancer Res 1999;59:3180–3184.
21. Pass HI, Robinson BW, Testa JR, Carbone M. Emerging translational therapies for mesothelioma. Chest 1999;116:455S–460S.