CD99 is a 32kDa transmembrane glycoprotein, also known as MIC2 (M = monoclonal; IC = Imperial Cancer Research Fund; 2 = order of discovery) and HBA71 antigen, which is thought to be involved in cell adhesion processes. The genes are located at chromosomes Xp22.32pter and Yq11pter. CD99 was first described in T-cell acute lymphoblastic leukaemia. Epstein-Barr virus latent membrane protein downregulates CD99, which has been shown to play a critical role in the formation of Hodgkin's and Reed-Sternberg cells. CD99 is found in testicular Sertoli cells and Leydig cells, ovarian granulosa cells, pancreatic islet cells, a subset of cortical thymocytes, immature terminal deoxynucleotidyl transferase (TdT)-positive T cells and a small group of myeloid precursor cells as well as in fibroblasts, endothelial cells, urothelium, some columnar and squamous epithelial cells, and ependymal cells.


CD99 has been detected in almost all cases of Ewing's sarcoma/pPNET*, solitary fibrous tumour, meningioma and T-cell acute lymphoblastic lymphoma/leukaemia. Most sex cord-stromal tumours are CD99+. A number of other tumours have shown positivity in a varying proportion, e.g., fibromatous tumours (such as calcifying aponeurotic fibroma, nuchal-type fibroma, giant cell angiofibroma, myofibroblastom, superficial acral fibromyxoma, atypical fibroxanthoma, mesenchymal chondrosarcoma, “haemangiopericytoma” and “malignant fibrous histiocytoma”), synovial sarcoma, small cell osteosarcoma, giant cell tumour of bone, rhabdomyosarcoma, acute and chronic myeloid leukaemia, precursor B-lymphoblastic lymphoma, gastrointestinal stromal tumour (GIST), perineuroma (myxoid sclerosing type) , Wilm’s tumour, thermoplastic small round cell tumour, glial tumours (particularly ependymoma), carcinoid, islet cell tumour, small cell carcinoma, metaplastic breast carcinoma, sarcomatoid renal cell carcinoma, and some cases of adenocarcinoma (gastric intestinal adenocarcinoma, hepatocellular carcinoma). The staining reaction is membranous and cytoplasmic in Ewing’s sarcoma/pPNET* and ependymoma, while a mainly cytoplasmic staining is seen in other tumours. In ependymoma, a cytoplasmic dot pattern may also be revealed. CD99 is usually not detected in lymphomas, sarcomas or carcinomas apart from the above mentioned. *peripheral primitive neuroectodermal tumour (peripheral neuroepithelioma).


CD99 is useful in the differential-diagnosis of small blue cell tumours of childhood, particularly for the identification of Ewing's sarcoma/pPNET. CD99 also might aid in the differential-diagnosis of genital tract neoplasms (identification of sex cord-stromal tumour) and spindle cell tumours.


Esophagus is recommended as positive control: The basal squamous epithelial cells must show an at least moderate distinct membranous staining while no cytoplasmic staining should be seen in the intermediate and superficial cells.

Selected references

Baker RJ, Hildebrandt RH, Rouse RV, Hendrickson MR, Longacre TA. Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex-cord-like elements. Hum Pathol. 1999 Jun;30(6):671-9. Gordon MD, Corless C, Renshaw AA, Beckstead J. CD99, keratin, and vimentin staining of sex cord-stromal tumors, normal ovary, and testis. Mod Pathol 1998;11(8):769-73. Jung KC, Park WS, Bae YM, Hahn JH, Hahn K, Lee H, Lee HW, Koo HJ, Shin HJ, Shin HS, Park YE, Park SH. Immunoreactivity of CD99 in stomach cancer. J Korean Med Sci. 2002 Aug;17(4):483-9. Milanezi F, Pereira EM, Ferreira FV, Leitao D, Schmitt FC. CD99/MIC-2 surface protein expression in breast carcinomas. Histopathology. 2001 Dec;39(6):578-83. Ramani P, Rampling D, Link M. Immunocytochemical study of 12E7 in small round-cell tumours of Histopathology. 1993 Dec;23(6):557-61. Weidner N & Tjoe J. Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Am J Surg Pathol 18:486-94 (1994).

19.03.10 - BR/MV/LE