Saturday, June 28, 2008

CD30 - a lymphoma defining molecule

CD30 was originally defined as a member of the nerve growth factor receptor superfamily, but more recently has been redefined as a cell membrane protein of the tumor necrosis factor receptor family. The textbooks say this about it: It has five clearly identifiable Cys-rich repeats. The structure is interrupted after repeat 3 by a hinge sequence of about 60 amino acids. It first became important as a marker for Hodgkin's disease. Although, clearly a malignant disease, the majority of the cells in the Hodgkin's lymph node were not monoclonal. They were a mixture of T cells, B cells, macrophages and eosinophils, and all part of a reaction against the tumor. The tumor cells are the large, binucleate Reed-Sternberg cells - mononuclear forms also exist, though they are more difficult to identify. Years ago the nature of the Reed Sternberg (R-S) cell in Hodgkin's disease was unclear, but they stained with antibodies against CD30, and it was using this label that enabled scientists to manipulate single cells to discover what exactly they were. We now know that R-S cells are B cells, crippled B cells, to be sure, but B cells nevertheless. It is now clear that what is crippling the B cells is either a mutation in the immunoglobulin genes that makes the production of immunoglobulin impossible (such as a stop codon) or else an abnormality that inactivates the immunoglobulin gene promoter such as a deficiency of the octamer dependent transcription factor, Oct2, or its coactivator, BOB.1.

CD30 became an important marker for identifying Hodgkin's disease and there are even attempts to treat Hodgkin's disease with anti-CD30 antibodies and immunocongugates. But reliance of CD30 was shattered when it became apparent that not all CD30 positive lymphomas were Hodgkin's disease. Anaplastic large cell lymphoma (ALCL) is a T cell lymphoma consisting of cells that are large with abundant cytoplasm and often horseshoe-shaped nuclei. The cells are CD30 positive and usually stain for an enzyme - the anaplastic large cell lymphoma kinase (ALK). It accounts for 3% of adult non-Hodgkin's lymphomas and about 10-30% in children. It is about 6 times more common in males than females, especially in younger individuals. It involves the lymph nodes, but also skin (21%), bone (17%), soft tissues (17%), lung (11%), and liver (8%). In 30% of cases it can be detected in the bone marrow. Three-quarters of patients show systemic symptoms.

The ALK gene is on chromosome 2 and in most cases there is genetic interference with this gene, most commonly by the formation of a conjoined gene with the gene for nucleophosmin (NPM)caused by the t2;5 translocation. NPM protein is normally found in teh nucleus of the cell, and this is teh way that ALK gets into the nucleus. There are other translocations with for example chromosomes, 1. 3, 17 or 19, but as these do not involve NPM, the ALK stays in the cytoplasm.

ALK positive lymphomas usually require treatment with chemotherapy, but the response rate is high and the 5-yeas survival about 80% Some ALCLs are ALK negative and these have a worse prognosis.

ALCL has to be distinguished from primary cutaneous anaplastic large cell lymphoma (C-ALCL). The cells here are CD30 positive but ALK negative. It is defined by being confined to teh skin as a tumor, nodule or papule. The diagnosis is confirmed by an extensive search that demonstrates that teh disease is not elsewhere. Treatment is by surgery or local radiotherapy and teh prognosis is very good.

CD30 may also be present on a variety of very rare lymphomas including Primary Effusion Lymphoma seen mainly in AIDS patients and associated with HHV8 infection, Lymphomatoid Granulomatosis, which is an angiocntric and angiodestructive lymphoproliferative disorder comprising EBV positive B cells and reactive T cells, and Celiac Disease-related T-cell Lymphoma.

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