Page 397 - Textbook of Pathology, 6th Edition

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Figure 14.24 Schematic diagram showing molecular pathogenesis CHAPTER 14
of multiple myeloma and its major manifestations.

Etiology and Pathogenesis 4. IL-6 cytokine plays a central role in cytokine-mediated
signaling and causes proliferation as well as cell survival of
Myeloma is a monoclonal proliferation of B-cells. The etiology tumour cells via its antiapoptotic effects on tumour cells.
of myeloma remains unknown. However, following factors
and abnormalities have been implicated: 5. Certain cytokines produced by myeloma cells bring about
bony destruction by acting as osteoclast-activating factor (OAF).
1. Radiation exposure. Large dose exposure to radiation These are: IL-1, lymphotoxin, VEGF, macrophage inhibitory
with a long latent period has been seen in myeloma. For factor-1α (MIP-1α), receptor activator of NF-κB ligand, and
instance, survivors of nuclear attack in World War-II tumour necrosis factor (TNF).
developed myeloma about 20 years later. 6. Other effects of adhesion-mediated and cytokine-mediated
2. Epidemiologic factors. Myeloma has higher incidence in signaling are development of drug resistance and migration of
blacks. Occupational exposure to petroleum products has tumour cells in the bone marrow milieu.
been associated with higher incidence. Certain occupations
such as farmers, wood workers and leather workers are more MORPHOLOGIC FEATURES. Myeloma affects princi-
prone. pally the bone marrow though during the course of the
3. Karyotypic abnormalities. Several chromosomal disease other organs are also involved. Therefore, the Disorders of Leucocytes and Lymphoreticular Tissues
alterations have been observed in cases of myeloma, which pathologic findings are described below under two
include following translocations and deletions: headings—osseous (bone marrow) lesions and extraosseous
i) Translocations t(11;14)(q13;q32) and t(4;14)(p16;q32). lesions.
ii) Deletion of 13q. A. OSSEOUS (BONE MARROW) LESIONS. In more
4. Oncogenes-antioncogenes. Overexpresion and muta- than 95% of cases, multiple myeloma begins in the bone
tions in following genes have been noted in proliferation of marrow. In majority of cases, the disease involves multiple
tumour cells in myeloma: bones. By the time the diagnosis is made, most of the bone
i) Overexpression of MYC and RAS growth promoting marrow is involved. Most commonly affected bones are
oncogenes in some cases. those with red marrow i.e. skull, spine, ribs and pelvis,
ii) Mutation in p53 and RB growth-suppressing antioncogene but later long bones of the limbs are also involved
in some cases. (Fig. 14.25). The lesions begin in the medullary cavity,
Based on above, the molecular pathogenesis of multiple erode the cancellous bone and ultimately cause
myeloma and its major manifestations can be explained as destruction of the bony cortex. Radiographically, these
under and is schematically illustrated in Fig. 14.24: lesions appear as punched out, rounded, 1-2 cm sized
1. Cell-surface adhesion molecules bind myeloma cells to bone defects in the affected bone.
marrow stromal cells and extracellular matrix proteins. Grossly, the normal bone marrow is replaced by soft,
2. This binding triggers adhesion-mediated signaling and gelatinous, reddish-grey tumours. The affected bone
mediates production of several cytokines by fibroblasts and usually shows focal or diffuse osteoporosis.
macrophages of the marrow. These include: IL-6, VEGF, Microscopically, the diagnosis of multiple myeloma can
TGFβ, TNF-α IL-1, lymphotoxin, macrophage inhibitory be usually established by examining bone marrow
factor-1α (MIP-1α) and receptor activator of nuclear aspiration from an area of bony rarefaction. However, if
factor-κB (RANK) ligand. the bone marrow aspiration yields dry tap or negative
3. Adhesion-mediated signaling affects the cell cycle via results, biopsy of radiologically abnormal or tender site
is usually diagnostic. The following features characterise
cyclin-D and p21 causing abnormal production of myeloma a case of myeloma:
(M) proteins.