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2010, Volume 26, Number 3, Page(s) 189-195
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DOI: 10.5146/tjpath.2010.01023 |
The Role of D2–40, and Podoplanin in Differentiating Mesotheliomas from Primary Adenocarcinomas of the Lung and Metastatic Carcinomas of the Pleura |
Seda GÜN1, Bedri KANDEMİR2, Mehmet KEFELİ2, Levent YILDIZ2, Sancar BARIŞ2, Filiz KARAGÖZ2 |
1Department of Pathology, Samsun Mehmet Aydın Education and Research Hospital, SAMSUN, TURKEY
2Department of Ondokuz Mayıs University, Faculty of Medicine, SAMSUN, TURKEY |
Keywords: Mesothelioma, Lung neoplasms, Adenocarcinoma, Metastasis, D2-40, Podoplanin, MOC-31 |
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Objective: The aim of this study was to assess the diagnostic
and differential significance of two recently introduced positive
mesothelial markers, namely podoplanin and D2-40.
Material and Method: The study group included a total of 55 cases: 11
cases of malignant mesothelioma and equal number of cases (n:11)
of primary lung adenocarcinoma, bronchioloalveolar carcinoma,
metastatic carcinoma of the pleura and mesothelial proliferation. D2-
40, podoplanin, calretinin, cytokeratin 5/6, carcinoembryonic antigen,
epithelial specific antigen (MOC-31) were immunohistochemically
studied in all cases. The extent of staining was graded between 1+
and 4+.
Results: While the 7 (63.6%) of the mesotheliomas and 10 of the
mesothelial proliferations (90.9%) stained positive with D2-40,
no positive staining was noted in primary lung adenocarcinoma,
bronchioloalveolar carcinoma, metastatic carcinoma of the pleura. 9
of the mesotheliomas (81.8%) and 10 of the mesothelial proliferations
(90.9%) were positive with podoplanin whereas no positive staining
was observed in the other groups. Eight of the primary lung
adenocarcinomas (72.7%), seven of the bronchioloalveolar carcinomas
(63.6%), and eight of the metastatic carcinomas of the pleura (72.7%)
were positive for MOC-31 while only one of the mesotheliomas (9%)
was positive and no mesothelial proliferation cases were positive. The
specificity of podoplanin, D2-40, calretinin and cytokeratin 5/6 for
mesothelioma was 100% and their sensitivity was 81.8%, 63.6%, 81.8%
and 54.5%, respectively. The highest sensitivity, (i.e. 100% sensitivity)
for mesothelioma was observed with the D2-40, podoplanin, and
calretinin combination.
Conclusion: D2-40 and Podoplanin were effective in differentiating
malignant mesothelioma from primary lung adenocarcinomas,
bronchioloalveolar carcinoma and metastatic carcinomas of the
pleura. However, since they may not yield precise results it was
therefore concluded that a panel combined with positive and negative
mesothelial markers including these two markers will lead to more
accurate results. |
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Malignant mesothelioma, first defined by Wagner in 1960
is a primary tumor that develops from mesothelial cells
on the serosal surfaces, especially on the pleura 1. Mesotheliomas
can display various cytomorphological and
histological types. It is difficult to differentiate them, both
macroscopically and microscopically, from primary lung
adenocarcinomas and metastatic carcinomas involving
pleura. Histochemical, immunohistochemical and electron
microscopic methods are employed when clinical, radiological
and histomorphological findings are not adequate
for differential diagnosis 2.
Today, there is no clearly defined marker for mesothelioma
3. The immunohistochemical diagnosis of mesothelioma
is generally possible with the panels composed of markers
often synthesized in mesotheliomas (positive mesothelioma
markers) and markers widely synthesized in carcinomas
(negative mesothelioma markers) 3-5. In the present
study, we combined positive mesothelial markers, calretinin
and cytokeratin (CK) 5/6 and negative mesothelial markers
carcinoembryonic antigen (CEA) and MOC-31, with
recently defined positive mesothelioma markers, D2-40
and podoplanin, and aimed to investigate their diagnostic
value in the differentiation of malignant mesothelioma from
primary lung adenocarcinomas and metastatic carcinomas
of the pleura. |
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Abstract
Introduction
Methods
Results
Disscussion
References
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55 cases from Ondokuz Mayıs University Medical School,
Department of Pathology obtained between 1988 and 2008
were included in the study. Patients’ diagnoses belonged
to one of the following 5 groups with 11 patients in each:
Malignant mesothelioma, primary lung adenocarcinoma,
bronchioloalveolar carcinoma, metastatic carcinoma of
the pleura and mesothelial proliferation. Paraffin sections
of the cases were re-evaluated and 4-micrometer sections
were prepared from the appropriate paraffin blocks that
represented the tumor best. The immunohistochemical
study was performed using the streptavidin biotin
peroxidase method with the primary antibodies D2-40
(monoclonal mouse, clone D2-40, DAKO, Carpinteria,
USA), podoplanin (18H5, sc-59347, Santa Cruz, California,
USA), CEA (monoclonal mouse, clone CD66e Ab-3,
Thermo Scientific, CA, USA), epithelial specific antigen Ab-
7 (monoclonal mouse, clone MOC 31, Thermo Scientific,
CA, USA), calretinin (rabbit, clone SP13, Thermo Scientific,
CA, USA), and cytokeratin 5/6 Ab-2 (monoclonal mouse,
clone D5/16 B4, Labvision, CA, USA). The epithelial cells in
thymus for D2-40, germinal central lymphocytes in tonsilla
pallatina for CEA and MOC 31, colonic adenocarcinoma
for calretinin and CK 5/6, pleural tissue sections for
podoplanin were used as positive controls. MOC 31, CEA
and calretinin were ready-for-use antibodies. Podoplanin,
D2-40 and CK 5/6 were diluted at the rates of 1/50, 1/100
and 1/20 respectively. Endogenous peroxidase activities
of the deparaffinized sections were blocked by incubating
in 3% hydrogen peroxide solution for 10 minutes. The
sections were boiled in citrate buffer for 35 minutes and
left to cool before studying with antibodies except CK
5/6. For CK 5/6 the sections were incubated in trypsin
for 15 minutes. Sections were processed with the primary
antibodies MOC 31, CEA, calretinin and CK 5/6 for 1 hour,
D2-40 for 2 hours and podoplanin for 18 hours. They were
then incubated with biotin-added anti-immunoglobulin
and streptavidin-peroxidase conjugate for 10 minutes. A
kit (DAKO, Carpinteria, USA) including 3.3’-diamino
benzidine (DAB) was used as the staining agent. Finally,
the sections were stained with Mayer‘s hematoxyline for 60
seconds. All sections were washed with pH 7.6 phosphate
buffer in every step up to the DAB application and washed
with distilled water after the DAB. All procedures were
performed at room temperature.
The results were evaluated under the Leica HMLB45
(Leica, Germany, 2000) light microscope. Cell membrane
staining for D2-40, podoplanin and MOC 31, cytoplasmic
and luminal membrane staining for CEA and cytoplasmic
staining for calretinin and CK 5/6 were accepted as
positive. The evaluation of the staining extent was made
semiquantitatively and scored according to the following
staining criteria (% of stained cells)=0%, negative; 1+ (1-
25%); 2+ (26-50%); 3+ (51-75%); and 4+ (76-100%).
Statistical evaluation of the results was performed with the
software “SPSS 12.,0 for Windows”. Mann-Whitney-U and
Wilcoxon Signed Ranks tests were used for the statistical
evaluation and p<0.05 was considered significant. The
sensitivity and specificity in differentiating malignant
mesothelioma from primary lung adenocarcinomas was
assessed for each mesothelial marker. |
Top
Abstract
Introduction
Methods
Results
Disscussion
References
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D2-40: Seven of the 11 (63.6%) malignant mesothelioma
cases were positive for D2-40. Of these, staining was 4+ in
2, 3+ in 1, 2+ in 1 and 1+ in 3 of the cases. The staining
was mostly continuous and apical along the cytoplasmic
membranes, while intracytoplasmic staining was rarely
noted (Figure 1A- D). No positive staining was observed in
other malignancy groups. Ten (90.9%) of the mesothelial
proliferation cases were positive. Of these, staining was
scored 4+ in 3, 3+ in 2 and 2+ in 5 of the cases. The staining
pattern was similar to that of mesothelioma. When the D2-40 positiveness in mesothelioma cases was compared with
those of primary lung adenocarcinomas, bronchioloalveolar
carcinoma and metastatic carcinomas of the pleura the
difference was found to be significant (p<0.05) (Table I). No
significant difference was observed when compared with
mesothelial proliferations (p>0.05).
Podoplanin: Nine of the 11 (81.8%) mesothelioma cases
were positive for podoplanin. Scoring was 4+ in 1, 3+ in 5
2+ in 1 and 1+ in 2 of the cases. The staining was continuous
and apical membranous along the cytoplasmic membranes
with rare cytoplasmic and nuclear staining (Figure 2A-D).
No positiveness was observed in other malignancy groups.
Ten (90.0%) of the mesothelial proliferation cases of the
podoplanin group were positive. Of these, staining was 4+
in 3, 3+ in 2 and 2+ in 5 of the cases. The staining pattern
was similar to that of mesothelioma. When the podoplanin
staining in malignant mesothelioma cases was statistically
compared with those of primary lung adenocarcinomas
bronchioloalveolar carcinoma and metastatic carcinomas
of the pleura the difference was significant (p<0.05) (Table I). There was no statistically significant difference between
mesothelial proliferations and mesotheliomas (p>0.05).
Calretinin: Nine of the 11 (81.8%) mesothelioma cases were
positive for calretinin. The staining was scored 4+ in 5, 3+
in 1 and 1+ in 3 of the cases. Both nuclear and cytoplasmic
staining was observed in all cases. No positiveness was
observed in other malignancy groups. Ten (90.9%) of the
mesothelial proliferation cases were positive. The staining
was 4+ in 1, 3+ in 4, 2+ in 4 and 1+ in 1 of the cases. The
pattern of the staining was similar to that of mesothelioma.
When statistically compared with those of primary lung
adenocarcinomas, bronchioloalveolar carcinoma and
metastatic carcinomas of the pleura the difference was
significant (p<0.05). There was no statistically significant
difference between the mesothelial proliferations and
mesotheliomas (p>0.05).
CK 5/6: Six of the 11(54.5%) mesothelioma cases were
positive for CK 5/6. Of these, staining was 3+ in 2 and 1+ in 4
of the cases. Cytoplasmic staining was observed in all cases.
No positiveness was observed in other malignancy groups.
Of the mesothelial proliferation cases, 9 (81.8%) were
positive. Staining was scored 2+ in 1 and 1+ in 8 of the cases.
Staining characteristic was similar to that of mesothelioma.
When malignant mesothelioma cases were compared
with primary lung adenocarcinomas, bronchioloalveolar
carcinoma and metastatic carcinomas of the pleura the
difference was statistically significant (p<0.05) (Table I).
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Figure 1: D2-40 expression in malignant mesothelioma (A,B, x200; C, x400). D2-40 was negative in primary lung adenocarcinoma (D, x200). |
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Figure 2: Podoplanin expression in malignant mesothelioma (A x100; B, x200; C, x400). Podoplanin negativity in primary lung adenocarcinoma (D, x200). |
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Figure 4: MOC-31 expression in bronchioloalveolar carcinoma (MOC 31, x400). |
When mesotheliomas and mesothelial proliferations were
compared for D2-40, podoplanin, calretinin and CK 5/6
no significant difference was observed (p>0.05).
CEA: Ten (90.9%) of the primary lung adenocarcinoma
cases were positive for CEA. Staining was scored 4+ in 5
3+ in 3 and 2+ in 2 of the cases. Mostly, cytoplasmic and
luminal membrane staining was observed (Figure 3). Nine
(81.8%) of the bronchioloalveolar carcinoma cases were
positive. In 4 of the cases, staining was 4+, 2+ in 2 cases
and 1+ in 3 cases. Staining characteristic was similar to
that of adenocarcinoma. Eight (72.7%) of the metastatic
carcinomas of the pleura were positive. Staining was scored
4+ in 4, 3+ in 1, 2+ in 1 and 1+ in 2 of the cases. One (9%) of
the mesothelioma cases was positive and its staining score
was 2+.
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Table I: p values obtained by the comparison of mesothelioma and primary lung adenocarcinomas for D2-40, podoplanin calretinin and CK 5/6 expression scores |
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Table II: p values obtained when the staining percentages of D2-40 and podoplanin in differentiating malignant mesothelioma from primary lung adenocarcinoma compared with the percentages of other positive mesothelial markers |
MOC-31: Eight (72.7%) of the primary lung adenocarcinoma
cases were positive for MOC-31. Staining scores were 4+ in
3, 3+ in 1, 2+ in 2 and 1+ in 2 of the cases. Staining was
observed mostly along the cell membrane. Seven (63.6%)
of the bronchioloalveolar carcinoma cases were positive.
Staining scores were 4+ in 1, 2+ in 1 and 1+ in 5 (Figure 4). Eight (72.7%) of the metastatic carcinomas of the pleura
were positive. Staining was scored 4+ in 2, 3+ in 3, 2+ in 2 and
1+ in 1 of the cases. The staining characteristic was similar
to that of adenocarcinoma. One (9%) of the mesothelioma
cases was positive and its staining score was 1+.
None of the mesothelial proliferation cases were positive for
CEA or MOC-31.
When D2-40 and podoplanin staining extent for
mesothelioma were compared with each other and compared
together with positive mesothelial marker calretinin, no
statistically significant staining difference was observed
(p>0.05). When CK 5/6 and podoplanin was compared
there was a statistically significant difference. When the
mean values were evaluated, it was observed that podoplanin
exhibited more staining extent in mesotheliomas (Table II).
The specificity and sensitivity for each positive mesothelial
marker were assessed by excluding the mesothelial
proliferations and the results were shown in Table III.
Specificity for all mesothelial markers was 100% when
mesothelial proliferations excluded while it was 77.3% when
it was included. The highest sensitivity for mesothelioma
was observed with the combination of podoplanin, D2-40
and calretinin and the combination of podoplanin, D2-40
CK 5/6 and calretinin.
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Table III: Specificity and sensitivity of positive mesothelial markers in differentiating malignant mesothelioma from primary lung adenocarcinomas |
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Top
Abstract
Introduction
Methods
Results
Disscussion
References
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Differentiation of malignant mesotheliomas from lung
adenocarcinomas and metastatic carcinomas of the pleura
can be very difficult, even impossible, under the light
microscope due to the similarity of their histomorphological
characteristics. A wide variety of markers have been used
in differentiating malignant mesothelioma from primary
lung adenocarcinomas 3-9. The differential diagnosis
has been based on the principal that the markers that are
positive in the cells of lung adenocarcinomas are negative
in mesothelial cells. The primary markers used for this
purpose are CEA, CD 15 (Leu M1), B72.3, Ber-Ep4, Bg 8
E-cadherin and MOC-31 2-5,7,10. A variety of markers
that are widely synthesized in malignant mesotheliomas but
not in primary lung adenocarcinomas have been defined in
recent years. Some of these markers are calretinin, CK 5/6
WT-1, mesothelin, HBME-1, OC-125, thrombomodulin
podoplanin and D2-40 7,10,11.
No specific marker for mesothelioma has been defined
yet 7,8,10. Various immunohistochemical panels have
therefore been used to differentiate mesothelioma from
primary lung adenocarcinomas and other metastatic
carcinomas of the pleura. There is a consensus that these
immunohistochemical panels should be composed
of both positive and negative mesothelioma markers
3,7,8,10,12. Yet, there is no general agreement on a certain
immunohistochemical panel 7,8,10.
There have been some recently published studies on the
significance of podoplanin, a transmembrane mucoprotein
which has been used as an immunohistochemical marker in
the diagnosis of mesothelioma 11-13. The results of these
studies have shown that podoplanin is often synthesized in
epithelioid mesotheliomas but not generally synthesized in
sarcomatoid mesotheliomas 11,13. The reported positivity
in epithelioid mesotheliomas ranges between 86% and
100% 7; the staining characteristics have been defined
to be along the apical surface of the cells and membranous
12,13. Kimura et al. 14 reported that podoplanin was
synthesized in all of the 5 epithelioid mesotheliomas but not
synthesized in any of the 93 adenocarcinomas of different
origins and claimed that this marker can be helpful in
differentiating mesotheliomas and adenocarcinomas. In our
study, 9 of the 11 (81.8%) mesotheliomas were positive for
podoplanin. There was no positivity in other malignancy
groups.
Recent studies have revealed that D2-40 can be helpful
in differentiating primary lung adenocarcinomas and
mesothelioma because it is often synthesized in epithelioid
mesotheliomas 8,11,13,15. Chu et al. investigated the
significance of D2-40 as a mesothelioma marker in 2005.
In their study, a membranous staining was reported in
the epithelioid components of 15 (94%) of the 16 biphasic
mesotheliomas and in all of the 33 (100%) epithelioid
mesotheliomas 13. In 2 studies in which different
mesothelioma groups were included, Ordonez reported
membranous D2-40 positivity in 37 of 40 (93%) and in 25
of 29 (86%) epithelioid mesotheliomas and argued that D2-
40 is one of the most sensitive and specific markers in the
diagnosis of epithelioid mesothelioma 11. In our study, 7
of the 11 (63.6%) mesotheliomas were positive for D2-40.
No positivity was observed in other malignancy groups.
In parallel with the literature, the results of our study revealed
that podoplanin and D2-40 have gained significance in
the differential diagnosis of malignant mesothelioma and
primary lung adenocarcinomas.
Ordonez et al. 11,15 established in 2 comparative studies
that podoplanin exhibits a sensitivity and specificity
similar to that of D2-40 in the diagnosis of mesothelioma.
Similarly, we observed no statistically significant difference
between podoplanin and D2-40 in differentiating malignant
mesothelioma and primary lung adenocarcinomas and
observed that they have similar sensitivity and specificity.
Calretinin is one of the first positive mesothelioma markers
found to be useful in the diagnosis of mesothelioma
7,8. It has been defined as one of the most specific and
the most sensitive of the current positive mesothelioma
markers 7,8,10 and has therefore been proposed as one
of the primary markers to be used in various panels used
in the diagnosis of mesothelioma 10. Nine of 11 (81.8%)
mesothelioma cases were positive with calretinin in our
study. The first study revealing that CK 5/6 might be useful
in differentiating lung adenocarcinomas and mesotheliomas
was by Blobel et al. in 1985 16. The reported positive
staining was 64-100% in epithelioid mesotheliomas 3,5,17
0-19% in lung adenocarcinomas 3,5,9,17 and 25-35%
in serous carcinomas 8. Six of 11 (54.5%) mesothelioma
cases were positive with CK 5/6 in our study. There was no
positivity in other malignancy groups.
CEA is the first generally accepted immunohistochemical
marker used in differentiating epithelioid mesotheliomas
from lung adenocarcinomas 18. Due to its high
sensitivity and specificity, CEA is still considered as the
best immunohistochemical marker in differentiating these
two tumor groups 8. Ten (90.9%) of the primary lung
adenocarcinomas and 9 (81.8%) of the bronchioloalveolar
carcinoma cases were positive for CEA in our study. But
only 1 (9%) mesothelioma was positive with CEA.
Due to its high sensitivity and specificity, researchers have
defined MOC 31 as the best negative mesothelioma marker
which can be used in differentiating pleural mesotheliomas
from both lung adenocarcinomas and lung squamous
carcinomas, and peritoneal mesotheliomas from serous
carcinomas 7,8. In parallel with the literature, only 1
(9%) mesothelioma case was positive with MOC 31 in our
study. On the other hand, 8 (72.7%) of the primary lung
adenocarcinomas and 7 (63.6%) of the bronchioloalveolar
carcinoma cases were positive.
No certain specific and sensitive marker has been defined
for mesotheliomas 2-5. Various immunohistochemical
panels including more than one marker have therefore
been composed 7,8,10. From a practical aspect, a
panel composed of 4 markers, 2 positive and 2 negative
mesothelial markers, would allow to differentiate malignant
mesothelioma from primary lung adenocarcinomas 2-5,7,8,10.
In our study, when the combination of D2-40 and
podoplanin and the combination of D2-40, podoplanin
and CK 5/6 were used as positive mesothelioma markers
separately, positive results were observed in 10 (90.0%) of
the 11 cases. However, when the combination of D2-40
podoplanin and calretinin and the combination of D2-40
podoplanin, CK 5/6 and calretinin were used, all (100%) the
cases were stained and the highest sensitivity was obtained.
Our results indicate that CK5/6 can be substituted with D2-
40 for improved sensitivity.
When the information obtained from the literature
and the results of our study are considered together, it
can be concluded that a single marker is not enough to
differentiate mesotheliomas from lung adenocarcinomas
bronchioloalveolar carcinomas and metastatic carcinomas
of the pleura, and that a panel should be formed with
positively and negatively staining mesothelioma markers.
In our opinion, a panel formed with podoplanin, D2-40
calretinin and CK 5/6 as positive mesothelial markers
together with the negative mesothelial markers CEA and
MOC-31 will be more conclusive in problematic cases. |
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Abstract
Introduction
Methods
Results
Discussion
References
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1) Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 1960, 17: 260-271 [ DOI: 10.1136/oem.17.4.260 ] [ PubMed ]
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Abstract
Introduction
Methods
Results
Discussion
References
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