While the onco-foetal antigen M2A was identified as a 40 kDa O-glycosylated glycoprotein recognized by the D2-40 Ab in foetal gonocytes and Sertoli cells, podoplanin was first identified as a 38 kDa transmembrane glycoprotein in the podocytes of rat kidney. Immunohistochemical studies of transfected cells have subsequently shown that M2A and podoplanin, also designated Aggrus, gp36 and T1A-2, are most likely identical proteins. Podoplanin acts as receptor for selectins (which mediate inflammatory cell adhesion) and is involved in cell maturation and migration by filopodia formation (via the downregulation of the activities of small Rho family GTPases). Podoplanin has also been identified as a platelet aggregation-inducing factor. Podoplanin is found in lymphatic endothelium (but not blood vessel endothelium), fibroblasts, osteocytes. follicular dendritic cells, smooth and striated muscle cells, myoepithelial cells, Cajal cells, basal cells in squamous epithelium (tonsil), gastric crypt cells, prostatic basal cells, immature Sertoli cells and foetal gonocytes (but not the corresponding cells of the adult testis), renal glomerular podocytes, mesothelium (particularly when reactive), subsets of lymphocytes, Schwann cells, glial and ependymal cells.


Podoplanin is demonstrated in virtually all cases of seminoma/dysgerminoma (but not in spermatocytic seminoma) as well as in pre-invasive precursor testicular germ cell neoplasia (carcinoma in situ or intratubular germ-cell neoplasia, IGCN). Embryonal carcinoma may show a more limited membranous reaction. Podoplanin is found in the large majority of epithelioid and biphasic malignant mesothelioma (~90%), adenomatoid tumour and synovial sarcoma (epithelioid part). Podoplanin is also demonstrated in virtually all cases of Kaposi sarcoma, furthermore in a subset of angiosarcoma, and the vacuolated cells of haemangioblastoma (while the endothelial cells of differentiated haemangiomatous tumours are always negative), in most cases of squamous cell carcinoma (head and neck, lung, uterine cervix), (myo-)fibroblastic tumours, leiomyosarcoma and gastrointestinal stromal tumour, almost all cases of chondromatous tumours (but not chordoma), follicular dendritic reticulum cell sarcoma, and in a large proportion of primary brain tumours (astrocytoma, glioblastoma, ependymoma, choroid plexus tumours, PNET, meningioma) Adenocarcinomas are usually negative. In serous carcinoma, the protein has been detected in 13-65% of the cases! In pleural effusions the frequency of podoplanin positive adenocarcinomas has been up to 50%.


Podoplanin is a very useful marker in the differentiation between malignant mesothelioma and adenocarcinoma (at least in histological specimens), and the identification of seminoma/dysgerminoma/IGCN (where it appears to be more sensitive and specific than, e.g., placental alkaline phosphatase, OCT3/4 and CD117). Podoplanin is also the primary choice in the visualization and quantification of lymphatic vessels and tumor invasion in the vessels (e.g., in the desmoplastic stroma of carcinomas, where both lymphangiogenesis and lymphatic tumour spread is associated with lymph node metastases and a worse prognosis).


Appendix is the recommended positive and negative tissue control for Podop. An at least moderate cytoplasmic staining of the Schwann cells in the muscularis propria of the appendix must be seen. In addition, endothelial cells of lymphatic vessels should be strongly stained, whereas no staining reaction should be seen in endothelial cells of the blood vessels and in the columnar epithelial cells and goblet cells of the mucosa.  

Selected references

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 Jul;30(7):878-82.
Biermann K, Klingmuller D, Koch A, Pietsch T, Schorle H, Buttner R, Zhou H. Diagnostic value of markers M2A, OCT3/4, AP-2gamma, PLAP and c-KIT in the detection of extragonadal seminomas. Histopathology. 2006 Sep;49(3):290-7.
Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol. 1999 Feb;154(2):385-94.
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.
Kazama S, Watanabe T, Ajioka Y, Kanazawa T, Nagawa H. Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2. Br J Cancer. 2006 Jan 30;94(2):293-8.
Okudera K, Kamata Y, Takanashi S, Hasegawa Y, Tsushima T, Ogura Y, Nakanishi K, Sato H, Okumura K. Small adenocarcinoma of the lung: prognostic significance of central fibrosis chiefly because of its association with angiogenesis and lymphangiogenesis. Pathol Int. 2006 Sep;56(9):494-502.
Ordonez NG. Podoplanin: a novel diagnostic immunohistochemical marker. Adv Anat Pathol. 2006 Mar;13(2):83-8. Ordonez NG. The diagnostic utility of immunohistochemistry in distinguishing between epithelioid mesotheliomas and squamous carcinomas of the lung: a comparative study. Mod Pathol. 2006 Mar;19(3):417-28.
Ordonez NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study. Mod Pathol. 2006 Jan;19(1):34-48.
Sonne SB, Herlihy AS, Hoei-Hansen CE, Nielsen JE, Almstrup K, Skakkebaek NE, Marks A, Leffers H, Rajpert-De Meyts E. Identity of M2A (D2-40) antigen and gp36 (Aggrus, T1A-2, podoplanin) in human developing testis, testicular carcinoma in situ and germ-cell tumours. Virchows Arch. 2006 Aug;449(2):200-6.
Urabe A, Matsumoto T, Kimura M, Sonoue H, Kinoshita K. Grading system of lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis in squamous cell carcinoma of the uterine cervix. Histopathology. 2006 Nov;49(5):493-7.
Walgenbach-Bruenagel G, Tolba RH, Varnai AD, Bollmann M, Hirner A, Walgenbach KJ. Detection of lymphatic invasion in early stage primary colorectal cancer with the monoclonal antibody D2-40. Eur Surg Res. 2006;38(5):438-44.
Yonemura Y, Endou Y, Tabachi K, Kawamura T, Yun HY, Kameya T, Hayashi I, Bandou E, Sasaki T, Miura M. Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2-40. Hum Pathol. 2006 Sep;37(9):1193-9.
Yuan P, Temam S, El-Naggar A, Zhou X, Liu DD, Lee JJ, Mao L. Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer. 2006 Aug 1;107(3):563-9.

14.11.12 - MV/LE