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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Utility of a highly specific and sensitive podoplanin/D2-40, calretinin, thyroid transcription factor-1, and carcinoembryonic antigen/CD66e immunohistochemical panel in differentiating malignant pleural mesothelioma from metastatic adenocarcinoma: An Egyptian experience

 Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

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Date of Submission19-Jun-2022
Date of Acceptance18-Jul-2022
Date of Web Publication14-Nov-2022


Background and Objective: Considering plentiful immunohistochemical (IHC) antibodies, a selection of highly sensitive and specific targeted panels is necessary to differentiate malignant pleural mesothelioma (MPM) from metastatic adenocarcinoma. We aimed to examine the sensitivity and specificity of four markers (podoplanin [PDPN]/D2-40, calretinin, thyroid transcription factor-1 [TTF-1], and carcinoembryonic antigen [CEA]/CD66e) as an initial IHC panel of Egyptian patients with malignant pleural biopsies. Materials and Methods: Forty Egyptian malignant pleural biopsies with histomorphological features of mesothelioma versus adenocarcinoma were immunohistochemically stained by PDPN/D2-40, calretinin, TTF-1, and CEA/CD66e. Results: PDPN/D2-40 and calretinin were positive in 27/27, 100% of mesothelioma cases with 100% sensitivity, 96.4% specificity for PDPN/D2-40, and 100% sensitivity and specificity for calretinin. Membranous PDPN/D2-40 expression was strong in 14 cases (53.85%), moderate in eight cases (30.77%), and weak in four cases (15.38%), while pure cytoplasmic staining was reported in one case. Calretinin was predominantly nuclear in all mesothelioma cases. TTF1 and CEA/CD66e were negative in all mesothelioma cases. In adenocarcinomas, PDPN/D2-40 was only expressed as weak cytoplasmic staining in 1/13 cases, while calretinin was negative in all 13 cases. Nuclear TTF1 and cytoplasmic CEA/CD66e immunostaining positivity were reported in all adenocarcinoma cases (13/13) with 100% sensitivity and specificity for both markers. Conclusion: The combination of PDPN/D2-40, calretinin together with CEA/CD66e, and TTF1 may be highly valuable in differentiating MPM from metastatic adenocarcinoma.

Keywords: Adenocarcinoma, carcinoembryonic antigen/CD66e, calretinin, mesothelioma, podoplanin/D2-40, thyroid transcription factor-1

How to cite this URL:
Khairy RA, Khaled E, El Sheikh S, Abdlaziz A, Khalifa SE. Utility of a highly specific and sensitive podoplanin/D2-40, calretinin, thyroid transcription factor-1, and carcinoembryonic antigen/CD66e immunohistochemical panel in differentiating malignant pleural mesothelioma from metastatic adenocarcinoma: An Egyptian experience. J Microsc Ultrastruct [Epub ahead of print] [cited 2023 Apr 1]. Available from: https://www.jmau.org/preprintarticle.asp?id=361124

  Introduction Top

The distinction of malignant pleural mesotheliomas (MPMs) from peripherally located lung adenocarcinomas and metastatic carcinomatous deposits of the pleura can be very problematic, even not possible using the routine light microscopy because of the resemblance of their histological features,[1] in addition to the fact that MPM commonly originates in the visceral pleura surrounding the lungs easily spreading to it.[2]

Given the impediments of routine histology, immunohistochemistry can be exceptionally valuable in making this distinction. The differentiation between histologic mimickers has been dependent on the assumption that the markers that are expressed in the cells of adenocarcinomas are negatively stained in mesothelial cells.[1] Several tumor markers are generally expressed in MPM but are negatively expressed in carcinoma are WT1, calretinin, keratin 5/6, thrombomodulin, and podoplanin (PDPN)/D2-40. Typically expressed markers in carcinoma and not expressed in mesothelioma are claudin-4, Ber-EP4, BG8, CD15, carcinoembryonic antigen (CEA), B72.3, MUC4, and MOC-31. Organ-associated immunohistochemical (IHC) markers that are frequently positively stained in metastatic carcinoma but show negative results in mesothelioma are thyroid transcription factor-1 (TTF-1) (lung and thyroid), napsin A (renal and bronchogenic), PAX8 (renal, müllerian, and thymic), CDX2 (gastric, intestinal, pancreaticobiliary), gross cystic disease fluid protein (breast), mammaglobin (breast), estrogen receptor (breast, müllerian), p63/p40 (squamous cell, urothelial), and GATA 3 (breast, urothelial, and squamous cell).[3]

Considering plentiful IHC markers, a selection needs to be made. That should depend on the clinical history, distribution of disease, and histologic features. Different targeted panels of mesothelial- and epithelial-specific markers were suggested.[4],[5]

The calcium-binding protein calretinin is regarded as a trustworthy marker for determining mesothelial primary origin. Its sensitivity is somewhat lower in sarcomatoid mesotheliomas, calretinin is not entirely specific for mesothelial cells; expression has been observed in some breast carcinomas, squamous cell carcinomas, serous ovarian carcinomas, renal cell carcinomas, ovarian sex cord-stromal tumors, and adrenocortical tumors. Calretinin is a defective mesothelial marker as a result. Despite being generally trustworthy and popular, it should be evaluated mostly among a wide-ranging immunopanel.[6]

PDPN/D2-40 is a Type I transmembrane glycoprotein that can be recognized by D2-40 antibody. It is selectively expressed in lymphatic endothelial cells, Type I alveolar epithelial cells, and podocytes of the glomeruli. PDPN is also upregulated in various tumors, including MPM, angiosarcomas, chondrosarcomas, osteosarcomas, germ-cell tumors, gliomas, glioblastomas, and squamous cell carcinomas.[7] It may also be expressed on the sarcomatoid subtype of MPM, but the positivity seems lower (30%–75%) as compared with epithelioid MPM (90%–100%).[8]

TTF-1 is a member of a homeodomain transcription factor family that is selectively expressed in the thyroid and lung epithelium.[9] It is very useful in the differential diagnosis of MPM versus lung adenocarcinoma involving the pleura. As up to eighty percent of lung adenocarcinomas show nuclear immunostaining (generally the nonmucinous variant of lung adenocarcinomas is positive). It is not immunostained in mesotheliomas.[10]

CEA/CD66e has a high reported specificity (90%–100%) and variable sensitivity (43%–100%) in detecting adenocarcinomas exhibiting a cytoplasmic staining pattern with membranous enhancement. While being negative in mesotheliomas.[11]

To our knowledge, no studies have been done in our country regarding the determination of a specific panel of antibodies dealing with a malignant pleural biopsy. Therefore, we aimed in this study to evaluate the pathologic value of PDPN/D2-40, calretinin, TTF-1, and CEA/CD66e as an initial IHC panel in differentiating mesothelioma and adenocarcinoma.

  Materials and Methods Top

This study was conducted after the approval of the Kasr Alainy Research Ethics Committee (REC) with an approval number of I-531019 in march 2019. All procedures performed were in accordance with the ICH GCP guidelines, and with the 1975 Helsinki declaration, as revised in 2008. Informed consent was obtained on admission.

Pleural samples that were included in the study were that of initial microscopic features suggesting MPM versus metastatic adenocarcinomas. Demographic and clinical data of all cases were summarized from the patients' files.

Immunohistochemical staining

Tumor sections of 4–5-μm thick were additionally re-cut and mounted onto SuperFrost plus slides to be examined for PDPN/D2-40, calretinin, TTF-1, and CEA/CD66e IHC staining.

The staining procedure was conducted using the Benchmark XT IHC/ISH staining module (Ventana, Medical Systems, Roche Group, California, USA).

For all cases, a negative control was obtained by omitting the primary antibodies.


Antibody against PDPN/D2-40 was obtained (ab109059, Abcam, UK). Antibody against PDPN/D2-40 was used at 1:200 dilutions. PDPN/D2-40 positivity in the endothelium of capillary lymphatic vessels served as an internal control. Cytoplasmic and membranous staining were considered positive by semiquantitative analysis. Immunostained cells were scored as: 1+ (ranging from 5% up to 25%), 2+ (starting from 26% up to 50%), and 3+ (exceeding 50%). When staining involves <5% of cells, this was considered negative. The intensity of immunostaining was evaluated as weak, moderate, or strong.[12]


A monoclonal mouse antibody (Calret 1, Dako, Glostrup, Denmark) at a dilution of 1:100 was used. Juvenile cystic granulosa cell tumor of the testis acted as a positive control. To establish a diagnosis of mesothelioma, positive cytoplasmic in addition to nuclear immunostaining for calretinin should be visualized. The cutoff values of 10% for cytoplasmic staining were accepted as positive staining.[8]

Thyroid transcription factor-1

Tumor sections were immunohistochemically tested for TTF-1, using mouse monoclonal class, clone SPT24 (diluted at 1:25, Novocastra, UK). Thyroid tissue sections were enrolled as a positive control. The results of immunostaining were interpreted as positive immunostaining or negative. Positive immunostaining was confirmed by moderate or strong nuclear positivity.[13]

Carcinoembryonic antigen/CD66e

IHC staining was done using clone COL-1(prediluted, Nichirei Bioscience, Tsukiji, Chuo-ku, Tokyo, 104-8402, Japan). Colon carcinoma was used as a positive control. Immunoexpression was recorded as either negative (if no staining was noted) or positive (membranous and/or cytoplasmic staining).[14]

Statistical analysis

The Statistical Package for the Social Sciences (SPSS) version 22.0 was used to analyze the collected data (IBM Corp., Armonk, NY, USA). Descriptive statistics were used in the statistical analysis. Results were presented as frequencies and percentages.

Standard diagnostic indices, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated as described by Galen (1980).[15]

  Results Top

A total of 40 pleural malignant biopsies were enrolled in this study, and a panel of IHC markers was conducted (PDPN/D2-40, Calretinin, TTF-1, and CEA/CD66e) to differentiate metastatic adenocarcinoma from MPM. Based on the conducted panel results, twenty-seven cases were confirmed to be MPM and 13 cases were confirmed to be metastatic adenocarcinoma.

Most patients diagnosed with MPM were ≥50 years old (19/27, 70.4%) with male predominance (20/27, 74.1%). Regarding the histopathologic variants of MPM; 25 cases were epithelioid, one case was sarcomatoid, and one case was biphasic.

Most studied cases of metastatic adenocarcinomas were above 50 years (10/13, 76.9%) and most of them were males (10/13, 76.9%).

Immunohistochemical panel results

PDPN/D2-40 was positively expressed in all cases of MPM (27/27) but negative in 92.3% of metastatic adenocarcinomas (1/13).

Calretinin was positively expressed mostly as strong nuclear with faint associated cytoplasmic staining in all cases of MPM (27/27) and was negative in 100% of metastatic adenocarcinomas (0/13).

TTF1 showed positive nuclear IHC expression in all cases of metastatic adenocarcinomas (13/13) but none of the MPM (0/27).

CEA/CD66e showed positive cytoplasmic/membranous IHC expression in 100% of metastatic adenocarcinomas (13/13) but was negative in all cases of MPM (0/27) [Figure 1], [Figure 2], [Figure 3].
Figure 1: (a) Positive membranous and cytoplasmic IHC staining of PDPN/D2-40 in sarcomatoid MPM (DAB, ×200). (b) Positive membranous immunohistochemical staining of PDPN/D2-40 in epithelioid MPM (DAB, ×200). (c) Positive nuclear immunohistochemical staining of calretinin in MPM (DAB, ×200). PDPN: Podoplanin, MPM: Malignant pleural mesothelioma, IHC: Immunohistochemical

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Figure 2: Positive membranous IHC staining of PDPN/D2-40 in MPM cases: (a) Strong membranous intensity, (b) Moderate membranous intensity, (c) Weak membranous intensity (DAB, ×200). PDPN: Podoplanin, MPM: Malignant pleural mesothelioma, IHC: Immunohistochemical

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Figure 3: (a) Positive nuclear immunohistochemical staining of TTF1 in metastatic adenocarcinoma (DAB, ×200). (b) Positive cytoplasmic immunohistochemical staining of CEA/CD66e in metastatic adenocarcinoma (DAB, ×200). TTF1: Thyroid transcription factor-1, CEA: Carcinoembryonic antigen

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[Table 1] summarizes the results of conducted IHC panel on the studied MPM and metastatic adenocarcinomas.
Table 1: Expression of Podoplanin/D2-40, calretenin, thyroid transcription factor-1, and carcinoembryonic antigen in malignant pleural mesothelioma and metastatic adenocarcinomas

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[Table 2] highlights the sensitivity, specificity, PPV, and NPV of conducted IHC panel in metastatic adenocarcinoma.
Table 2: Sensitivity, specificity, positive predictive, and negative predictive values of Podoplanin/D2-40 and calretinin in malignant pleural mesothelioma, thyroid transcription factor-1, and carcinoembryonic antigen/CD66e in metastatic adenocarcinoma

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In the MPM, 26/27 cases showed membranous PDPN/D2-40 staining; 14/27 cases showed cytoplasmic staining; 13 cases showed concomitant cytoplasmic and membranous staining. More than 50% (14/27) of MPM showed score 3+ PDPN/D2-40 expression. Strong intensity of PDPN/D2-40 staining was observed in membranous staining only (14 cases) [Table 3].
Table 3: Podoplanin/D2-40 immunohistochemical staining results in 27 studied malignant pleural mesothelioma cases

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  Discussion Top

According to the latest recommendations of the international mesothelioma interest group, the diagnosis of MPM should rely on both the morphologic features and immunohistochemistry results. The suggested IHC panel should be decided according to the initial morphologic features and should include both positively stained and negative tumor markers for mesothelial origin in addition to possible tumor mimickers. The proposed tumor markers should have either sensitivity or specificity exceeding 80% for the tumors in question. Analysis and interpretation of results of IHC staining should put into consideration the pattern of stain (e.g., nuclear, versus membranous, or cytoplasmic) and the percentage of positive cells (>10% is generally recommended).[8] A selected panel of tumor markers was enrolled in the current study to distinguish MPM from metastatic adenocarcinomas (PDPN/D2-40, calretinin, TTF-1, and CEA/CD66e). This panel was proposed as a practical diagnostic panel feasible in most Egyptian laboratories.

In the current study, PDPN/D2-40 was expressed in 27/27 (100%) of MPM with 100% sensitivity and 96.4% specificity. Similar figures were reported by Ordonez, in which the reactivity for PDPN was obtained in 25 (86%) of the 29 epithelioid mesotheliomas.[16] Padgett et al. reported a slightly lower figure where anti PDPN stained 84% of mesotheliomas (46/55), with a sensitivity of 84% and specificity of 99%.[17] Our figures are also similar to what was reported by Hanna et al., who found PDPN to be expressed in 94% of their MPMs, with membranous immunoreactivity recorded to be of high sensitivity and specificity for mesothelial cells.[12]

Regarding PDPN/D2-40 expression in mesothelioma variants, our study showed positive PDPN/D2-40 expression in 100% of all mesothelioma variants (25 epithelioid, 1 sarcomatoid, and 1 biphasic). In a study performed by Padgett et al. done on 55 mesotheliomas (24 epithelioid, 18 sarcomatoid, and 13 biphasic) using membranous or cytoplasmic staining as indicative of positivity, it was found that PDPN stained 84% of mesotheliomas (46/55) including 72% of sarcomatoid mesotheliomas (13/18), the findings of this study suggested that cytoplasmic PDPN expression may be useful in the diagnosis of sarcomatoid mesothelioma.[17] On the other hand, a study performed by Ordóñez, on 40 mesotheliomas (29 epithelioid, five biphasic, and six sarcomatoid) showed that none of the sarcomatoid mesotheliomas showed positive PDPN expression.[16] This discrepancy may be owed to different clones of antibodies used and different sample sizes.

In the present work, 96.3% (26/27) of the studied mesothelioma cases showed membranous PDPN/D2-40 staining pattern. Membranous staining intensity was strong in 14 studied cases (53.8%), moderate staining is seen in eight studied cases (30.8%), and the weak staining in four examined cases (15.4%). These figures are similar to those reported by Hanna et al. where >50% of their cases showed membranous staining, their immunostaining intensity was strong in eight studied cases (44%), moderate in five studied cases (28%), and weak in only four examined cases (22%).[12]

Thirteen MPM cases in the current work showed concomitant PDPN/D2-40 cytoplasmic with membranous staining and only one case showed pure cytoplasmic staining) of which; 11 cases (40.7%) of weak intensity and three cases (11.1%) of moderate intensity. Hanna et al. who studied PDPN expression in cell blocks of collected 86 samples of pleural effusions reported close figures with only 28% of cases showing cytoplasmic staining pattern: (6%) moderate cytoplasmic staining intensity and (22%) weak cytoplasmic staining intensity.[12]

In the highlights of the previous results, together with other studies, membranous PDPN immunostaining was superior to cytoplasmic staining in the diagnosis of mesothelioma, especially epithelioid variant.

Regarding calretinin expression in mesothelioma cases, the current study showed positive Calretinin expression in 100% of all mesothelioma variants (25 epithelioid, one sarcomatoid, and one biphasic); this figure was in agreement with Comin et al., in which 42/42 mesothelioma cases were stained for calretinin (100%).[18] Slightly lower figures were reported by Chhieng et al. in which 14 of 16 cases; (87.5%) were positive for calretenin.[19] Different sample sizes and different clones of used antibodies may be the cause of different results.

Regarding TTF1 and CEA/CD66e expression in mesothelioma cases, the current study showed negative expression in 100% of all mesothelioma cases, this figure is similar to that was reported by Di Loreto et al.,[20] in which TTF-1 immunoreactivity was identified in none of the 24 cases of mesothelioma and slightly differed from that was reported by Comin et al.,[18] in which 42 mesothelioma cases were stained for CEA and only 4 (9.5%) mesothelioma cases stained for CEA this difference may be due to different staining techniques or due to differences in the antibody used.

Comparing PDPN/D2-40 sensitivity and specificity in mesothelioma with other markers that are used to diagnose mesothelioma, it was found that, in the current study PDPN/D2-40 showed 100% sensitivity and 96.4% specificity, calretinin showed 100% sensitivity and 100% specificity. This comes in agreement with Yaziji et al. where calretinin had the best sensitivity for mesothelioma (95%), followed by other markers such as WT-1 (78%), cytokeratin 5 (76%), mesothelin (75%), vimentin, and thrombomodulin (68%).[21] On the other hand, Yaziji et al.[21] reported that thrombomodulin had the best specificity for mesothelioma (92%), followed by cytokeratin 5 (89%), calretinin (87%), and vimentin (84%). Padgett et al.[17] reported slightly lower figures for PDPN; sensitivity (84%) and specificity (99%). Li et al.[22] also reported lower sensitivity (91%) and specificity (96%) for calretinin.

In the studied adenocarcinoma cases, only one case showed positive PDPN/D2-40 expression (1/13, 7.7%); this figure is similar to that reported by Ordóñez,[16] and Padgett et al.,[17] in which negative PDPN immunostaining was noted in all cases of pulmonary adenocarcinoma (0/34) and (0/80), respectively. Moreover, Ordóñez,[16] reported negative PDPN immunostaining in all cases of nonpulmonary adenocarcinoma (0/80).

PDPN/D2-40-positive tumor cells have proved to be of invasive potential due to recruitment of platelet aggregation, which enhances metastasis, acquisition of altered cell morphology, kinetics, and epithelial–mesenchymal transformation.[23],[24] Accordingly, investigations are crucial to understand the molecular mechanisms of PDPN/D2-40 expression and to develop novel treatment strategies in the management of tumors with PDPN/D2-40-positive cells.[25]

Moreover, another study reported that blocking the expression of the gene encoding PDPN promoted the number of tumor cells undergoing apoptosis.[26]

In the present work, a single case of adenocarcinoma showed positive PDPN/D2-40 cytoplasmic expression; score +1 (in <25% of tumor cells); this figure is similar to that reported by Hanna et al.,[12] in which 1/14 cases of adenocarcinoma (7%) demonstrated PDPN cytoplasmic staining in <25% of tumor cells.

Our study and that of Hanna et al.[12] revealed the absence of membranous PDPN/D2-40 staining in all cases of metastatic lung adenocarcinoma.

Regarding calretinin expression in adenocarcinoma cases, in the current study, none of the adenocarcinoma (0/13) cases showed calretinin expression, this figure is similar to that was reported by Chhieng et al.[19] in which 15 metastatic adenocarcinoma cases were stained for calretinin and all specimens were classified as negative for calretinin, and differs from that reported by Comin et al.,[18] in which 2/23 cases of pulmonary adenocarcinomas were stained with anticalretinin antibodies, (8.7%) cases; this difference may be due to the different number of cases, different staining technique or due to differences in the antibody used.

Regarding TTF1 and CEA/CD66e expression in adenocarcinoma cases, in the current study, all studied cases of adenocarcinoma were positive for TTF1 and CEA/CD66e; this figure differs from that was reported by Di Loreto et al.,[20] in which TTF-1 immunoreactivity was identified in 19 of 33 cases of AC (57.5%) due to the different number of cases, and slightly similar to that was reported by Comin et al.,[18] in which 23 cases of pulmonary adenocarcinomas were stained with CEA and 22 out of them (95.6%) showed positivity for CEA.

  Conclusion Top

To sum up, from the studied results, membranous immunostaining for PDPN/D2-40, in combination with nuclear calretinin, might be very useful in distinguishing MPM from metastatic adenocarcinomatous deposits of different origins such as renal, bronchogenic, mammary, and ovarian if combined with cytoplasmic CEA/CD66e and, nuclear TTF1 because of their high sensitivity and specificity; more than 90% for PDPN/D2-40 and 100% for calretinin, CEA/CD66e, and TTF1. In addition, further studies are encouraged to validate the role of PDPN/D2-40 as a potential prognostic tumor biomarker in MPM and as a therapeutic target.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Mohammad T, Garratt J, Torlakovic E, Gilks B, Churg A. Utility of a CEA, CD15, calretinin, and CK5/6 panel for distinguishing between mesotheliomas and pulmonary adenocarcinomas in clinical practice. Am J Surg Pathol 2012;36:1503-8.  Back to cited text no. 4
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Correspondence Address:
Sara E Khalifa,
Department of Pathology, Faculty of Medicine, Cairo University, 17 Emtedad Al Aml Al Maadi, Cairo 11728
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmau.jmau_51_22


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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