Immunophenotypical (IP) differential diagnosis and immunobiology of childhood primary brain tumors. A decade of experience

Cancer associated markers represent the biochemical or immunological counte rparts of the morphology of tumors. The expression of an immunocytochemical ly defined cancer associated marker is also related to the tissue of origin and is not a random event. During the past two decades, the use of MoABs against oncofetal, neoplasm a ssociated, cell lineage specific, endothelial, and cell proliferation relat ed antigens in the diagnosis and biological assessment of prognosis in neop lastic disease gained increased importance. A sensitive direct correlation exists between the expression of certain molecules and the development of a n invasive, highly malignant immunophenotype (IP) of neoplastic cells, acco mpanied by pathobiological events such as angiogenesis and metastasis. Our systematic and detailed cellular IP analyses of 82 childhood brain humo rs [34 medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs), 42 astrocytomas (ASTRs), 5 choroid plexus papillomas (CPPs) and 1 choroid ple xus carcinoma (CPC)], was conducted using over 55 MoABs. An indirect, four- step, enzyme linked [alkaline phosphatase (AP) and peroxidase], biotin-stre ptavidin based, antigen detection technique was employed. Our results allowed us to draw the following significant conclusions: (1) P NETs, ASTRs, CPPs, and CPCs display a heterogeneous IF; (2) both differenti ated and immature neurofilament proteins are present in the great majority of childhood primary brain tumors; (3) gliomas, MEDs, and PNETs co-express GFAP, NF-H, NF-M, vimentin, and at least one cytokeratin; (4) neuronal diff erentiation is always present within childhood brain tumors; (5) neoplastic ally transformed astrocytes may be able to present antigens to infiltrating T lymphocytes since MHC molecules are expressed on their surfaces; (6) MHC class I and Il molecules are not present on normal astrocytes in vivo, whe reas in vitro cultured astrocytes express MHC class I and II molecules, esp ecially after interferon-gamma preincubation; (7) 65/76 PNETs and ASTRs con tained tumor infiltrating leukocytes (TIL), particularly the cytotoxic, MHC class I-restricted and tumor associated antigen (TAA)-specific and directe d, CD8(+) lymphocyte clone, representing the functionally compromised effec tor cells of the host's cellular immunological response; (8) granulocytes a nd premyelocytes participate among the TIL, probably as a response to intra tumoral inflammation and necrotic changes; (9) the growth of solid neoplasm s, including childhood brain tumors, even at clinically undetectable sizes (a few mm(3)), as well as the generation of an invasive cellular immunophen otype (CIP) in neoplastic cells and distant metastases depends upon the con tinuous formation of new blood capillaries; (10) the newly organized tumor blood capillaries' most striking feature is the presence of markedly enlarg ed and disorganized perivascular spaces, measuring at least 2-5mm, detected in all observed childhood primary brain tumors and was independent of the tumor's size, as well as its morphological and cellular differentiation fea tures; (11) endothelial cells undergo rapid proliferation during neoplasm r elated and induced neo-vascularization which can be demonstrated immunomorp hologically by the detection of the cell surface localized endoglin (EDG/CD 105), a transforming growth factor-beta (TGF-beta) receptor and a prolifera tion-associated antigen (PAA) expressed on endothelial cell surfaces; (12) inhibition of angiogenesis as a form of anti-neoplastic therapy has been an d should be extensively studied; (13) brain tumor cells often express an ap optosis related transmembrane glycoprotein Fas/APO-l (CD95), a member of th e nerve growth factor/tumor necrosis receptor superfamily, which is not pre sent on normal cells in the CNS (apoptosis being trigerred by the binding o f Fas/APO-1 to its natural ligand (Fas-L/APO-1L)); (14) further studies sho uld substantiate the importance of CD105 or EDG in the earliest possible de tection, diagnosis and neoplasm related angiogenesis inhibition-based treat ment of mammalian solid neoplasms, especially childhood brain tumors; (15) future observations of immunobiology, cell cycle regulation and endothelial cell proliferation should aid in the development of individualized, fourth modality, immunotherapeutical regimens for primary childhood brain tumors.