D2-40, oncofetal M2A antigen
D2-40 was initially considered to
be directed against the M2A antigen, a 40 kDa O-linked sialoglycoprotein
found on the cell surface of testicular gonocytes, germ cell tumours lymphatic
endothelium and mesothelial cells. Using a human podoplanin-Fc fusion
protein, it has been shown that the commercially available mouse monoclonal
antibody D2-40 specifically recognized human podoplanin,
as assessed by enzyme-linked immunosorbent assay and Western blot analyses8.
D2-40 is immunoreactive with formalin-fixed
paraffin embedded tissue.
Immunohistochemical expression
The lymphatic staining is in a thin linear
pattern: unlike CD31 and CD34,
blood vessel endothelium is negative.
The basal layer of sebaceous glands and
outer root sheath of hair follicles stain.
Kaposi sarcoma stains, suggesting derivation
from lymphatics.
| |
|
D2-40 |
CD31 |
|
| |
Lymphangioma |
10/106, 10/107 |
5/106, 5/107 |
|
Haemangioma |
0/106 0/227 |
10/106, 27/277 |
Spindle
cell haemangioma |
1/57 |
|
Glomus tumour |
0/36, 0/57 |
0/36, 0/57 |
Angiolipoma |
0/26 |
2/26 |
Pyogenic
granuloma |
0/26 |
2/26 |
Vascular
malformation |
0/26 |
2/26 |
Reactive
angioendotheliomatosis |
1/1 |
1/17 |
Vascular
transformation of lymph node |
1/17 |
1/17 |
Dabska
tumour |
3/37 |
3/37 |
Haemangiopericytoma |
0/16 |
1/1(Endothelial
cells were positive and pericytes were negative.)6 |
Epithelioid haemangioendothelioma |
0/16, 1/107 |
1/16, 10/107 |
Retiform
haemangioendothelioma |
0/17 |
1/17 |
Kaposiform
haemangioendothelioma |
0/17 |
1/17 |
Cutaneous
Kaposi sarcoma |
24/24(cases
included patch, plaque and nodular stages)6,
9/107 |
24/24(positivity
was weak)6,
9/107 |
Angiosarcoma |
3/76, 7/157 |
7/76, 15/157 |
Neurofibroma |
0/66 |
|
Dermatofibroma |
2/66 |
|
Dermatofibrosarcoma
protuberans |
0/46 |
|
Leiomyosarcoma |
3/106 |
|
Malignant fibrous histiocytoma |
1/26 |
|
| |
|
|
Mesothelial immunoreactivity is membranous
and, to a lesser extent, cytoplasmic. Other antibodies are shown for comparison.
| |
|
D2-40 |
Calretinin |
WT1 |
CK5/6 |
|
| |
rate of positivity |
mean percentage of cells staining
in positive cases |
|
Mesothelioma |
epithelioid |
33/331,
32/45(the
lower sensitivity may have been because this was a tissue microarray
based study.)5, 84/112(epithelioid
mesotheliomas studied by TMAs)11 |
92%1 |
33/331, 104/112(epithelioid mesotheliomas
studied by TMAs)11 |
19/331 |
29/321 |
biphasic |
15/161, 96/162(epithelioid
areas of biphasic mesotheliomas studied by TMAs)11, 39/120(sarcomatoid
areas of biphasic mesotheliomas studied by TMAs)11 |
epithelioid cells: 90%, sarcomatous
cells: 26%1 |
16/161, 148/164(epithelioid areas of
biphasic mesotheliomas studied by TMAs)11, 70/121(sarcomatoid
areas of biphasic mesotheliomas studied by TMAs)11 |
10/161 |
13/161 |
sarcomatous |
3/41, 11/46(sarcomatoid
mesotheliomas studied by TMAs)11 |
52%1 |
2/41, 25/46(sarcomatoid mesotheliomas
studied by TMAs)11 |
0/41 |
1/41 |
Reactive pleura |
27/281 |
71%1 |
|
|
|
Pulmonary adenocarcinoma |
2/31(weak cytoplasmic staining)1 |
13%1 |
7/311 |
2/311 |
12/311 |
Ovarian serous carcinoma |
17/26(membranous staining)1 |
33%1 |
8/261 |
23/261 |
9/261 |
Renal cell carcinoma |
Conventional |
0/161 |
|
2/161 |
0/161 |
5/161 |
Papillary |
5/13(weak cytoplasmic staining)1 |
43%1 |
1/131 |
1/131 |
7/131 |
Chromophobe |
0/51 |
|
1/51 |
1/51 |
1/51 |
Breast carcinoma |
3/16(weak cytoplasmic staining)1 |
13%1 |
|
|
|
Prostatic adenocarcinoma |
0/111 |
|
|
|
|
Urothelial carcinoma |
0/71 |
|
|
|
|
| |
|
|
|
|
|
|
Calretinin has a greater sensitivity than does D2-40 in both epithelioid
and sarcomatoid mesotheliomas but it is useful to combine them in a panel:
| |
Sensitivities: |
epithelioid |
sarcomatoid |
|
calretinin |
0.91 |
0.57 |
D2-40 |
0.66 |
0.3 |
positivity for calretinin or D2-40 |
0.96 |
0.66 |
Another study evaluated podoplanin alongside D2-402:
| |
|
|
D2-40 |
Podoplanin |
|
Mesothelioma |
epithelioid |
25/29(better differentiated
tumours show thick continuous membrane staining. In poorly differentiated
tumours, membrane staining is discontinuous or staining is dot-like.
Intracytoplasmic globoid staining may occur.) |
25/29(staining was seen
in the same 25 cases that showed positivity with D2-40) |
biphasic |
4/5(positivity confined
to the epithelioid component) |
4/5(positivity confined
to the epithelioid component) |
sarcomatoid |
0/6 |
0/6 |
Adenocarcinoma |
lung |
0/24 |
0/24 |
ovary |
0/17 |
0/17 |
endometrium |
0/5 |
0/5 |
breast |
0/10 |
0/10 |
pancreas |
0/5 |
0/5 |
stomach |
0/5 |
0/5 |
colon |
0/10 |
0/10 |
kidney |
0/10 |
0/10 |
prostate |
0/5 |
0/5 |
thyroid |
0/3 |
0/3 |
Adenomatoid tumour |
2/2(staining is of the
apical cell membrane) |
2/2 |
Squamous
carcinoma of lung |
0/10 |
0/10 |
Angiosarcoma |
2/5 |
2/5 |
Synovial sarcoma |
biphasic |
4/6(positivity confined
to the epithelioid component) |
4/6(positivity confined
to the epithelioid component) |
monophasic |
0/6 |
0/6 |
| |
|
|
|
This study was based on cell blocks prepared from serous effusions3. In cases where tumours stained,
the pattern was membranous.
| |
|
up to 10% of tumour cells staining |
more than 10% of tumour cells staining |
|
reactive mesothelium |
|
153/153(8
purely reactive, 145 mesothelial cells in the presence of malignancy) |
malignant mesothelioma |
2/32(24 pleura, 8 peritoneal) |
30/32(24 pleura, 8 peritoneal) |
malignant mesothelioma biopsies |
|
12/12 |
ovarian carcinoma |
85/169(138 serous [including
23 primary peritoneal and 8 tubal], 3 clear cell, 3 endometrioid,
7 undifferentiated, 6 combined, 2 undefined: 129 peritoneal, 40
pleural) |
13/169(138 serous [including
23 primary peritoneal and 8 tubal], 3 clear cell, 3 endometrioid,
7 undifferentiated, 6 combined, 2 undefined: 129 peritoneal, 40
pleural) |
ovarian microarray of biopsies |
5/7272 cores of primary
and metastatic ovarian carcinoma from 23 patients) |
9/7272 cores of primary
and metastatic ovarian carcinoma from 23 patients) |
breast carcinoma |
11/44(40 pleura, 3 peritoneal) |
2/44(40 pleura, 3 peritoneal) |
adenocarcinoma of unknown origin |
3/14(7 pleural, 7 peritoneal) |
3/14(7 pleural, 7 peritoneal) |
lung carcinoma |
2/6(all pleural) |
0/6(all pleural) |
Other cancers(4
oesophagus, 4 cervix uteri, 2 endometrial, 3 gastric, 1 colon,
1 pancreas, 1 prostate, 1 melanoma) |
7/17(2/2 cervical, 1/2
endometrial, 1/3 gastric, 2/4 oesophageal, 1/1 pancreatic, 1/1
prostatic and 1/1 melanoma were positive) |
2/17(2/2 cervical, 1/2
endometrial, 1/3 gastric, 2/4 oesophageal, 1/1 pancreatic, 1/1
prostatic and 1/1 melanoma were positive) |
| |
|
|
Primary
cutaneous carcinomas are commonly positive while metastases to skin are
negative:
| |
primary skin tumours |
Sebaceous carcinoma |
10/10(diffusely positive
in 6 cases, focally positive in 4 cases)9, 2/29 |
|
Squamous cell carcinoma |
10/10(diffusely positive
in 8 cases, focally positive in 2 cases)9 |
Porocarcinoma |
4/4(diffusely positive
in 1 case, focally positive in 3 cases)9, 2/29 |
Trichilemmal carcinoma |
4/4(focally positive in
all 4 cases)9 |
Sweat gland adenocarcinoma |
1/19 |
Adenoid cystic carcinoma |
0/19 |
Skin adnexal carcinoma NOS |
4/4(diffusely positive
in 4 cases, focally positive in 4 cases)9, 0/1(poorly
differentiated adnexal carcinoma)9 |
Atypical adnexal tumour |
1/19 |
Benign primary adnexal tumour |
38/46(diffusely positive
in 12 cases, focally positive in 26 cases. these cases consisted
of 14 sebaceous adenomas, 15 syringomas, 9 hidradenomas, 7 eccrine
poromas and 1 spiradenoma. sebaceous adenomas shows staining of
the basaloid cells. )9, 6/6(2
spiradenomas, 2 benign mixed tumours, 1 papillary hidradenoma,
1 nodular hidradenoma)9 |
| |
|
|
Carcinoma metastatic to skin |
0/15(the metastases were
from breast (6 cases), colon, lung, biliary tract, ovary, pancreas,
thyroid, and one retroperitoneal spindle cell sarcoma.)9,
1/21(0/6
lung, 0/5 breast, 0/2 colon, 1/1 renal, 0/1 gastric, 0/1 prostatic,
0/1 biliary, 0/1 ovarian, 0/1 bladder, 0/1 unknown primary)9 |
| |
|
|
Adenomatoid
tumour: 2/212
Diagnostic utility
Diagnosis of lymphatic-derived tumours. Positivity
may be helpful in differentiating Kaposi sarcoma from other vascular
lesions.
Diagnosis of lymphatic invasion by tumours. Lymphatic
invasion by breast carcinoma is predictive of distant recurrences
and shortened survival10.
Demonstration of lymphovascular invasion in colorectal carcinoma
may be more efficient than a search for micrometastases in the selection
of high-risk patients who may benefit from adjuvant therapy13.
Differentiation of mesothelioma
from adenocarcinoma4.
The initial evidence as to its usefulness in the differentiation of
mesothelioma
from serous ovarian tumours is inconsistent. Like other mesothelial
markers, it appears least useful in sarcomatous mesotheliomas.
Differentiation of primary skin adnexal carcinomas
from adenocarcinomas metastatic to the skin9.
References
1 Chu AY, Litzky LA,
Pasha TL, Acs G,Zhang PJ Utility of D2-40, a novel mesothelial marker,
in the diagnosis of malignant mesothelioma. Mod Pathol 2005; 18:105-10
2 Ordonez
NG D2-40 and podoplanin are highly specific and sensitive immunohistochemical
markers of epithelioid malignant mesothelioma. Hum Pathol 2005; 36:372-80
3 Bassarova
AV, Nesland JM,Davidson B. D2-40 is Not a Specific Marker for Cells of
Mesothelial Origin in Serous Effusions. Am J Surg Pathol 2006; 30:878-82
4
Ordonez
NG. Immunohistochemical diagnosis of epithelioid mesothelioma: an update.
Arch Pathol Lab Med 2005; 129:1407-14 FULL TEXT
5
SienkoA, Zander DS, Killen D et al. D2-40 is a novel new marker of malignant
mesothelioma (MM): tissue microarray study of 45 MM versus 409 lung carcinomas
and primary non-mesothelial neoplasm of the pleura and chest wall. Mod
Pathol 2005;18(suppl1):318A.
6 Kahn
HJ, Bailey D,Marks A. Monoclonal antibody D2-40, a new marker of lymphatic
endothelium, reacts with Kaposi's sarcoma and a subset of angiosarcomas.
Mod Pathol 2002; 15:434-40
7 Fukunaga
M. Expression of D2-40 in lymphatic endothelium of normal tissues and
in vascular tumours. Histopathology 2005; 46:396-402
8 Schacht
V, Dadras SS, Johnson LA, et al. Up-regulation of the lymphatic marker
podoplanin, a mucin-type transmembrane glycoprotein, in human squamous
cell carcinomas and germ cell tumors. Am J Pathol 2005; 166:913-21
FULL
TEXT
9
Liang
H, Wu H, Giorgadze TA, et al. Podoplanin is a highly sensitive and specific
marker to distinguish primary skin adnexal carcinomas from adenocarcinomas
metastatic to skin. Am J Surg Pathol 2007; 31:304-10
10
Arnaout-Alkarain
A, Kahn HJ, Narod SA, et al. Significance of lymph vessel invasion identified
by the endothelial lymphatic marker D2-40 in node negative breast cancer.
Mod Pathol 2007; 20:183-91
11
Hinterberger
M, Reineke T, Storz M, et al. D2-40 and calretinin - a tissue microarray
analysis of 341 malignant mesotheliomas with emphasis on sarcomatoid differentiation.
Mod Pathol 2007; 20:248-55
12 Kuroda
N, Toi M, Hiroi M, et al. Diagnostic pitfall of D2-40 in adenomatosid
tumour. Histopathology 2007; 51:719-21
13 Barresi
V, Reggiani Bonetti L, Vitarelli E, Di Gregorio C, Ponz de Leon M, Barresi
G. Immunohistochemical assessment of lymphovascular invasion in stage
I colorectal carcinoma: prognostic relevance and correlation with nodal
micrometastases. Am J Surg Pathol. 2012 Jan;36(1):66-72.
This page last
revised 6.3.2012.
©SMUHT/PW
Bishop