.png){kind=icon}
12.1 Blood cell morphology, immunophenotype, genotype, normal cell counterpart, site of origin, clinical aggressiveness, and prognosis.
12.2 IL.3, encoded by a gene located on chromosome 5q31, is upregulated when translocated to the IGH locus. IL3 can induce eosinophil differentiation, leading to increased numbers within the peripheral blood.
12.3 Ki-67 is expressed in all stages of the cell cycle except G0. The Ki-67 index is often over 95% in BL, showing that at any one time in excess of 95% of tumour cells are actively involved in cell cycling. Upregulation of c-Myc through the three typical translocations seen in BL can lead to abnormal control of cell growth, proliferation, induction of apoptosis, and metabolism. Secondary mutation of TP53 enhances the effect of MYC and enables tumorigenesis, and c-Myc upregulation leads to rapid cell cycling.
12.4 CLL has been divided into two distinct pathologies by the identification of differences in IGVH mutational status. CLL cells can either contain IGVH genes that are somatically hypermutated, showing <98% homology with germline sequences, or unmutated, with an excess of 98% homology. Cells showing somatic hypermutation are not as aggressive as unmutated CLL cells.
12.5 CNS DLBCL is associated with EBV in immunocompromised patients.
EBV + DLBCL of the elderly is EBV-positive by definition
DLBCL with chronic inflammation is associated with EBV
Lymphomatoid granulomatosis is associated with EBV
Plasmablastic lymphoma is associated with EBV and HIV
HHV8 MCD is associated with HHV8, EBV, and HIV
PEL is associated with HIV, HHV8, and EBV
12.6 t(14;18)(q32;q21) fuses the anti-apoptotic protein BCL2 with IGH. Following translocation, BCL2 is moved from its original locus 18q21 to the IGH locus at 14q32. The gain of BCL2 transcriptional control by the IGH promoter leads to overexpression of BCL2 and the inhibition of apoptosis and the accumulation of mature cells.
12.7 Gene expression profiling shows that hairy cells are derived from memory B-cells with abnormal isotype switching.
12.8 Immunophenotypically, MCL cells express a phenotype very similar to the CLL phenotype. Both cases express CD5, CD19, CD20. CD23 is expressed in CLL, but has variable expression in MCL. IgM and IgD are present on the cell surface of MCL, but surface immunoglobulin is not always present, or is weakly expressed, in CLL.
12.9 Increased NFkB signalling occurs in two ways:
API2–MALT1 mimics BCR signalling leading to increased downstream effects, including the activation of NFkB.
API2–MALT1 can indirectly activate NFkB leading to increased signalling.
The consequence of these interactions and upregulated NFkB is the overexpression of a range of target genes, many of which possess anti-apoptotic activity.
12.10 Evidence of a paraprotein using serum electrophoresis, and evidence of a monoclonal protein by immunofixation. Hypercalcaemia and raised serum creatinine and urinary Bence-Jones proteins may be found in plasma cell myeloma. Decreased serum immunoglobulins are found in the majority of patients. The patient may have a normochromic normocytic anaemia, neutopenia, and a raised ESR.
12.11 Soluble plasma-cell derivatives are responsible for myeloma-related bone disease. Secretion of IL-1 and TNFa by the malignant cells induces osteoblasts to synthesize and release MIP-1a. MIP-1a stimulates osteoclast proliferation. MIP-1a is also released by malignant plasma cells to the same effect. RANKL is synthesized and secreted by plasma cells and bone marrow stromal cells, resulting in the general upregulation of osteoclast activity and increased bone resorption. The osteoclast inhibitor OPG is down-regulated in myeloma.
12.12 ALK is a tyrosine kinase. When fused with NPM it becomes located within nuclear and cytoplasmic regions, and importantly becomes constitutively activated. Increased signalling through ALK leads to important downstream events, such as increased JAK3–STAT3 signalling.
12.13 HRS cells are derived from germinal centre B cells. There is evidence of somatic hypermutation in the majority of cases, although missense mutations are also involved in 25%. Somatic hypermutation places these cells within the germinal centre.