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101
CANCER
CYTOPATHOLOGY
Utility of the Antibodies CA 19-9, HBME-1, and
Thrombomodulin in the Diagnosis of Malignant
Mesothelioma and Adenocarcinoma in Cytology
Patricia A. Fetsch, M.T. (A.S.C.P.)
Andrea Abati, M.D.
Yasmine M. Hijazi, M.D.
BACKGROUND. The distinction between malignant mesothelioma (MM) and adenocarcinoma (ACA) in cytologic specimens frequently is difficult, often requiring
immunocytochemistry to support the diagnosis. Recent reports have proposed the
Laboratory of Pathology, Cytopathology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
utilization of antibodies to mesothelial cell clone HBME-1 and thrombomodulin
(TM), because they are immunoreactive in MM and less commonly reactive in
ACA. Immunoreactivity for the monoclonal antibody CA 19-9 has been observed
in many ACAs and reportedly is absent in MM.
METHODS. In this study, immunostaining was performed on formalin fixed, paraffin
embedded cell blocks from effusions or fine-needle aspirations using the avidinbiotin-peroxidase method. Thirty-eight MMs and 49 ACAs were tested using antibodies to CA 19-9, HBME-1, and TM.
RESULTS. Anti-CA 19-9 stained only 1 of the 37 cases of MM tested (3%), but
stained 24 of the 49 cases of ACA (49%). Anti-HBME-1 stained 34 of 38 cases of
MM (89%), and 28 of 43 cases of ACA tested (65%). Anti-TM stained 24 of 36 cases
of MM (67%), and 21 of 40 cases of ACA tested (53%).
CONCLUSIONS. CA 19-9 has utility as part of an immunocytochemical panel for
distinguishing ACA from MM, because a positive staining reaction would make
the diagnosis of MM unlikely. Although HBME-1 and TM can identify MM positively, each frequently is detected in ACA, thus limiting the utility of these antibodies in cytologic specimens. Cancer (Cancer Cytopathol) 1998;84:101–8.
q 1998 American Cancer Society.
KEYWORDS: CA 19-9, HBME-1, thrombomodulin, mesothelioma, adenocarcinoma,
immunocytochemistry.
P
Address for reprints: Andrea Abati, M.D., Cytopathology Section, National Institutes of Health/
National Cancer Institute, Bldg. 10, Room 2A19,
10 Center Drive MSC 1500, Bethesda, MD
20892-1500.
Received October 29, 1997; accepted November
10, 1997.
leural effusions may be the first manifestation of both mesotheliomas and metastatic adenocarcinomas. In these circumstances, cytology can play a pivotal role in the initial diagnosis. The differential
diagnosis of malignant mesothelioma (MM) from adenocarcinoma
(ACA) in cytologic specimens is aided greatly by immunocytochemistry. Because no specific antigen has been shown to be diagnostic for
distinguishing MM from ACA, the use of a panel of antibodies provides
the highest degree of accuracy. This panel most often includes antibodies to carcinoembryonic antigen (CEA), LeuM1, B72.3, BerEP4,
and epithelial membrane antigen (EMA), with markers for keratin and
vimentin also included in some laboratories.1 – 8 Positivity for CEA,
BerEP4, B72.3, or LeuM1 favors the diagnosis of ACA over MM.5,6,8,9
This study examined three additional markers (CA 19-9, HBME-1, and
thrombomodulin [TM]), which are believed by some authors to be of
clinical utility in surgical pathology specimens, and their diagnostic
utility in 87 cytologic specimens with a confirmed diagnosis of either
q 1998 American Cancer Society
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102
CANCER (CANCER CYTOPATHOLOGY) April 25, 1998 / Volume 84 / Number 2
MM or ACA.10 – 16 The diagnostic applications of these
antibodies in cytopathology specimens are as yet untested in the medical literature.
Anti-CA 19-9 is a monoclonal antibody directed
against alpha (2,3)-sialylated Lewis-a (Le-a), a blood
group antigen.10 Immunoreactivity for CA 19-9 has
been observed in many gastrointestinal (GI) primary
ACAs, but has been reported to be absent in MM.11
HBME-1 is an antibody raised against cultured
mesothelioma cells and recognizes an antigen on the
microvillus surface.12,13 It has been reported to be present in both MM and ACA, but with a different staining
pattern; MMs are said to have a ‘‘thick (bushy) membrane’’ pattern, whereas ACAs are found to have a
‘‘thin membrane’’ or a cytoplasmic staining pattern.12
TM is a transmembrane glycoprotein receptor,
located on the vascular endothelial cell surface. The
distribution of TM in normal tissue includes endothelial and mesothelial cells. It has been reported to
stain a majority of MMs and only a rare number of
ACAs.14 – 16
TABLE 1
Immunoreactivity of CA 19-9 in Malignant Mesotheliomas and
Adenocarcinomas
Malignant mesothelioma
Adenocarcinoma
Breast
Ovary
Prostate
Lung
GI
Positive
Negative
Total
1
36
37
8
5
0
3
8
7
3
5
7
3
15
8
5
10
11
GI: gastrointestinal.
(Sigma Chemical Co., St. Louis, MO) was used for detection. The tumor cells were evaluated for cytoplasmic and surface staining; HBME-1 surface staining
was described as either thick/bushy or thin. All slides
were interpreted by one pathologist (Y.M.H.).
MATERIALS AND METHODS
RESULTS
Formalin fixed, paraffin embedded archival cell block
material from 71 effusions and 16 fine-needle aspirates
was cut in 5-m sections and mounted on charged slides
(Fisher Scientific, Pittsburgh, PA). A total of 87 cell
blocks were studied; 38 were classified as MM and 49
as ACAs, which included 15 breast, 8 ovary, 5 prostate,
10 lung, and 11 GI primary sites. The diagnosis of each
case was confirmed by surgical excision and histologic
examination, immunohistochemical studies, and, in
some instances, electron microscopy. In three cases
of MM no surgical material was available; thus the
diagnosis was based on cytologic examination with
confirmatory immunocytochemistry and ultrastructural studies. The subclassification of the MM based
on histologic examination of the surgical material
available was: 28 epitheliod, 6 biphasic, and 1 sarcomatoid variant. Hematoxylin and eosin stained sections of each cell block were evaluated for the presence
of tumor. The unstained slides were deparaffinized
and immunostained using a modified avidin-biotinperoxidase technique (Vector Laboratories, Burlingame, CA). The primary antibodies CA 19-9 (Signet
Laboratories, Dedham MA; 1:2 dilution), HBME-1
(DAKO Corp., Carpinteria, CA; 1:50 dilution), and TM
(DAKO; 1:10 dilution) along with a negative control
(purified myeloma protein, mouse immunoglobulin
G1 kappa; Organon Teknika Corp., Durham, NC; 1:50
dilution) were run on each sample. No type of specimen pretreatment (i.e., digestion, microwave heating)
was performed as per the manufacturers’ recommendations. The chromogen 3,3*-diaminobenzidine
Thirty-seven cases of MM and 49 cases of ACA were
tested for reactivity with anti-CA 19-9 (Table 1). Positive reactivity was identified as surface staining of the
tumor cells. One case of MM (3%) reacted positively
with this marker. Approximately 49% (24 of 49) of the
ACAs tested were immunoreactive. Of the ACAs tested,
the following reacted positively: 8 of 15 breast ACAs
(53%), 5 of 8 ovarian ACAs (63%), 0 of 5 prostate ACAs
(0%), 3 of 10 lung ACAs (30%), and 8 of 11 GI ACAs
(73%).
The staining pattern with anti-HBME-1 was described as either thick/bushy membrane, thin membrane, or cytoplasmic (Table 2). Approximately 89%
(34 of 38) of MM reacted positively, with the majority
of these cases (82%) showing a thick/bushy membrane
staining pattern (28 of 34). Thin membrane staining
was present, but in a smaller proportion (6 of 34; 18%)
of the positive cases. Cytoplasmic staining was present
in 6 of 38 (16%) cases of MM, and was observed in
conjunction with either bushy or thin membrane
staining in all instances. Of interest, the staining for
HBME-1 was negative in four cases of MM: one sarcomatoid, two epithelioid, and one biphasic variant.
Similarly, ACAs reacted positively in 65% of cases (28
of 43), with the majority of these cases (18 of 28; 64%)
exhibiting a thick/bushy membrane staining pattern.
Thin membrane staining also was present, but in a
smaller proportion of the positively reacting cases (10
of 28; 36%). Of the ACAs, the following were immunoreactive: 9 of 15 breast ACAs (60%), 6 of 7 ovarian ACAs
(86%), 2 of 4 prostate ACAs (50%), 8 of 8 lung ACAs
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CA 19-9, HBME-1, and Thrombomodulin/Fetsch et al.
103
FIGURE 1. (a) Pancreatic adenocarcinoma exhibiting strong positivity for CA 19-9. (b) Malignant mesothelioma with no immunostaining
for CA 19-9 (hematoxylin and diaminobenzidine, 1200).
(100%), and 3 of 9 GI ACAs (33%). Cytoplasmic staining
was present in 6 of 43 cases of ACA (14%) and was
observed in conjunction with either bushy or thin
membrane staining in all but 1 case.
TM reactivity showed two distinct patterns of antigen localization: cell membrane and diffuse cytoplasmic. In all cases that reacted positively, both staining patterns were present (Table 3). Twenty-four of 36
MMs (67%) showed a positive staining reaction for TM
with both cell membrane and cytoplasmic patterns.
The ACAs tested showed a positive immunoreactivity
in 21 of 40 cases (53%), with a similarly mixed staining
pattern; 8 of 13 breast ACAs (62%), 2 of 6 ovarian ACAs
(33%), 1 of 4 prostate ACAs (25%), 4 of 8 lung ACAs
(50%), and 6 of 9 GI ACAs (67%) reacted positively. In
general, TM staining was less intense in ACA compared with MM.
DISCUSSION
Immunohistochemistry has contributed greatly to resolving the problems associated with the differential
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diagnosis of MM versus ACA. By demonstrating positivity to markers such as CEA, B72.3, LeuM1, EMA, and
BerEP4,1 – 8,17 – 21 a diagnosis of ACA can be confirmed
in a majority of cases. However, the diagnosis of mesothelioma most often is based on the absence of staining with these antibodies.5,15,17,22,23 Unfortunately, positive staining with these antibodies has been reported
in a small but significant percentage of MM.24 Additional dilemmas in cytology include the differentiation
of single cells in effusion specimens as being either
malignant or benign mesothelial cells, as well as the
distinction at times between single ACA cells and benign mesothelial cells.
Staining immunoreactivity in MM is observed
with several antibodies, although these antibodies
tend not to be specific for mesothelioma. Mesothelial
or mesothelioma cell antibodies currently being marketed are scarce, but are said to demonstrate a thick,
brush border-like membrane pattern that correlates
with the long microvilli of mesothelial and MM cells
observed on electron microscopy.25 These antibodies
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CANCER (CANCER CYTOPATHOLOGY) April 25, 1998 / Volume 84 / Number 2
FIGURE 2. Malignant mesothelioma with thick/bushy membrane positivity for HBME-1 (hematoxylin and diaminobenzidine, 1200).
include HBME-112 and TM,14 – 16 as well as calretinin,26
OV632,27 – 29 K1,30 ME-1,31 and a cytoplasmic protein of
mesothelial cells.32 However, the use of these probes
has been limited due to reports of low sensitivity and
specificity, inability for use in fixed/paraffin embedded tissues, or the lack of commercial availability.26,27,30 – 32
We studied three immunocytochemical markers
and their possible use in differentiating MM from ACA
in cytologic specimens. CA 19-9 is a blood group-related antigen that identifies sialylated Lewis-a, and was
first introduced as a GI and pancreatic specific tumor
antigen.11 It has been reported to be positive in GI
carcinomas, thyroid papillary carcinomas, and endometrial ACAs.12 Expression of CA 19-9 requires expression of the Lewis-a blood group antigen; in the Lewisa negative population, CA 19-9 is absent and therefore
cannot be applied as a tumor marker. Approximately
90% of the population possess the Lewis gene.33 Mesotheliomas, melanomas, and malignant fibrous histiocytomas have been found to be negative for CA 19-
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9.11 Our results substantiate this because only 1 of 37
MMs tested showed a positive reaction for CA 19-9
(confirmation of the diagnosis of MM in this case was
accomplished through ultrastructural studies).
Although only 24 of 49% ACAs (49%) reacted positively for CA 19-9, a positive staining pattern makes
the diagnosis of MM unlikely. However, of clinical significance, this antibody is of limited value in the differential diagnosis of pulmonary ACA and MM because
most pulmonary ACAs reportedly are nonreactive.11 In
our study all the positive cases of pulmonary ACA
(three) exhibited only focal or rare immunoreactivity
of tumor cells with anti-CA 19-9. Our findings support
those of previous studies that show CA 19-9 to be negative in MM,5,9,34with variable positive reactivity in extrapulmonary ACAs. CA 19-9 has been shown to be
expressed highly in GI ACAs but only exceptionally
positive in breast, kidney, and prostate carcinomas.11
Thus, CA 19-9 may be a useful adjunct as part of an
immunocytochemical panel for the distinction of ACA
from MM. It most likely is not helpful in predicting
the site of origin of metastatic ACA as was previously
stated, nor should it be used as the sole marker for
the distinction of MM from ACA.11
Anti-HBME-1 is a mouse monoclonal antibody
prepared from human mesothelial cells from patients
with malignant epithelial mesothelioma.12,13 Using immunohistochemical techniques, this antibody stains
normal mesothelial cells, epithelial mesotheliomas,
and various ACAs. It reportedly is nonreactive with
sarcomatous mesotheliomas or with the sarcomatous
components of the biphasic variants.12 It is interesting
to note that our four nonreactive cases were of variable
histologic morphology (one sarcomatoid, two epithelioid, and one biphasic variant). Originally, the staining
pattern had been described as ‘‘thick’’ membrane in
MM, and cytoplasmic with occasional ‘‘thin’’ membrane staining in ACA.7,35 Recent studies, including
ours, do not show such a distinctive difference12;
rather, there appears to be a ‘‘gradient’’ with MM in
the high range (i.e., thicker staining in the majority of
tumor cells in a given sample) and ACA in the middle
range (thick staining in a smaller proportion of tumor
cells in conjunction with thin staining). These findings
directly question the clinical utility of this antibody on
cytologic specimens with the differential diagnosis of
ACA versus MM.
Results of this study corroborate previous reports
in that a positive staining reaction with HBME-1 was
observed not only in MM but also in ovarian and lung
ACA, and was less commonly reactive in GI, breast,
and prostate ACA.12 However, our findings differ from
those of Savera et al. who reported that 91% of MM
showed a pattern of thick membrane staining with
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CA 19-9, HBME-1, and Thrombomodulin/Fetsch et al.
105
FIGURE 3.
(a) Adenocarcinoma of the lung in pleural effusion demonstrating thick/bushy membrane immunoreactivity for HBME-1. (b)
Gastrointestinal adenocarcinoma showing patchy thin membrane immunoreactivity for HBME-1. Note the thick membrane staining of the
mesothelial cell in the background (hematoxylin and diaminobenzidine, 1200).
HBME-1, whereas 66% of the cases of pulmonary ACA
tested showed reactivity with a thin/cytoplasmic staining pattern. They concluded that HBME-1 patterns
were sufficiently distinct to be useful in the diagnosis
of MM versus pulmonary ACA when used in a panel
of antibodies.35 Our results show only minor differences in staining patterns between MM and lung ACA
in the cytologic specimens assayed. To the contrary,
100% of pulmonary ACAs tested stained with HBME1, and 63% of these exhibited a thick/bushy staining
pattern.
TM is a glycoprotein that normally is present in a
restricted number of cells, including endothelial and
mesothelial cells as well as megakaryocytes, mesangial
cells, some squamous epithelial cells, and synovial
cells. The function of TM is to convert thrombin from
a procoagulant protease to an anticoagulant, shifting
thrombin activity toward the protein C pathway. Because TM is identical to fetomodulin, which modulates
embryogenesis, some authors have concluded that TM
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is an oncodevelopmental antigen.14 It has been reported to show a positive staining reaction in many
neoplasms, including MM and ACA.15 – 17 TM also has
been shown to be of utility in the identification of
vascular tumors, particularly angiosarcomas, as well
as choriocarcinomas.15
A distinct staining pattern with TM previously has
been reported: 1) thin membrane staining in benign
mesothelial cells, 2) thick membrane staining in MM,
and 3) cytoplasmic staining in carcinomas. The thick,
‘‘fluffy’’ membranes of MM cells reflect anti-TM selective labeling of microvilli, which are particularly prominent in MM.28
Ascoli et al. found TM immunoreactivity in all
MMs tested, with the distinctive brush-like membrane
being a typical finding of MM cells. They concluded
that a negative TM makes the diagnosis of MM unlikely, although 39% of ACAs tested also were positive.16 Collins et al. found that all the MMs tested
stained with TM, but only 8% of ACAs were positive,
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CANCER (CANCER CYTOPATHOLOGY) April 25, 1998 / Volume 84 / Number 2
FIGURE 4. (a) Malignant mesothelioma with immunostaining for thrombomodulin. (b) Adenocarcinoma of the lung with immunoreactivity
for thrombomodulin. Surface/membrane staining was more intense than cytoplasmic immunoreactivity in both cases (hematoxylin and
diaminobenzidine, 1200).
TABLE 2
Immunoreactivity of HBME-1 in Malignant Mesotheliomas and
Adenocarcinomas
Malignant mesothelioma
Adenocarcinoma
Breast
Ovary
Prostate
Lung
GI
Positive
Negative
Bushy
Thin
34
4
28
6
9
6
2
8
3
6
1
2
0
6
6
4
1
5
2
3
2
1
3
1
GI: gastrointestinal.
and that immunoelectron microscopy showed that TM
was distributed evenly on the cell surface, including
microvilli, in normal mesothelial cells, and mesothelioma cells.15 More recently, Doglioni et al. found TM
reactivity in 80% of MMs and 77% of pulmonary
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ACAs.26 In this study, two distinct patterns of antigen
localization were observed: cell membrane and diffuse
cytoplasmic. However, as was observed with HBME1, both patterns of staining were present in MMs as
well as ACAs. Of the MMs tested, 67% were positive
for TM; 56% of the ACAs were positive. Thus, based
on our results as well as those of Doglioni et al., we
would expect this antibody to be of limited utility for
the differential diagnosis of MM and ACA.
The multiple studies published describing the utility of various antibodies for distinguishing ACA from
MM in surgical and cytologic material have not always
been in agreement. The discrepancy in results may be
due in part to variations in type of specimen, specimen
preparation, fixation method, technique, overutilization of the antigen retrieval method, differences in sensitivity between laboratories, and the use of different
antibody clones recognizing various epitopes.36 We
have speculated that the variance in reactivity between
surgical and effusion cytologic material may be be-
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CA 19-9, HBME-1, and Thrombomodulin/Fetsch et al.
TABLE 3
Immunoreactivity of Thrombomodulin in Malignant Mesotheliomas
and Adenocarcinomas
8.
Malignant
mesothelioma
Adenocarcinoma
Breast
Ovary
Prostate
Lung
GI
Positive
Negative
Total
24
12
36
9.
8
2
1
4
6
5
4
3
4
3
13
6
4
8
9
10.
11.
GI: gastrointestinal.
12.
cause of the cells floating in a highly proteinaceous
solution yielding nonspecific staining.37 Our data suggest that CA 19-9 shows promise as a useful marker
for distinguishing MM from ACA (predominantly nonpulmonary) due to its relative absence in MM. Our
results also suggest that in cytologic material both
HBME-1 and TM can positively identify MM; however,
each is not infrequently detected in ACA, and therefore
staining is not selective for MM. Based on our results,
these antibodies have a limited utility as additions to
a panel directed at the differential diagnosis of MM
versus ACA in cytologic specimens.
As we look to the future, a number of new methodologies are being developed that apply cell biology
techniques to cytologic specimens. Through the use
of probes for specific numeric and structural abnormalities specific for different types of ACA and MM,
the current difficulties in distinguishing between these
two entities undoubtedly will be facilitated.7,38,39
13.
14.
15.
16.
17.
18.
19.
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