Pathology

The principal distinctive pathological features of HCL (Table 29.7) have been known for more than 20 years, but their pathogenesis has only recently started to be defined. Thus, the cell-signaling and gene-expression studies described above have now largely elucidated the causes of the unusual morphology of HCs. Also, investigations of the expression and function of adhesion receptors, together with the identification of patho-genetically important cytokines, have provided data that could explain the predilection of HCs for homing

Table 29.7 Key pathological feature of HCL

• Pathognomonic HC

• TRAP expression by HCs

• BM infiltration and fibrosis

• Invasion of splenic red pulp and pseudosinus formation

• Hepatic infiltration with sinusoidal and portal tract involvement

• Lymph nodes relatively spared

• Cytopenias (especially monocytopenia), T-cell dysfunction and immune defect to bone marrow, spleen and liver, while largely sparing other lymphoreticular sites.

CYTOLOGY AND (IMMUNO)CYTOCHEMISTRY OF HAIRY CELLS

In stained films of blood and bone marrow, HCs appear as distinctive large cells (15-30 ^m in diameter) with abundant light-blue cytoplasm and peripheral hair-like protrusions. The nucleus is usually eccentric and has relatively open chromatin with inconspicuous nucleoli. HCs are unique among hemic cells in displaying strong cytoplasmic staining for tartrate-resistant acid phosphatase. Both the surface appearance and TRAP positivity of HCs are the result of the intrinsic activation described earlier.

As at the level of the light microscope, the ultrastructure of HCs corresponds to that of highly meta-bolically active cells. Thus, HCs display only modest peripheral nuclear chromatin condensation and possess abundant cytoplasm with plentiful mitochondria and frequent ribosomes. A relatively specific ultrastructural feature is the presence of ribosome-lamellar complexes in a variable proportion of cells (Fig. 29.1). Although these structures were described many years ago,36 their nature and functions are still unclear. HCs contain a large amount of F-actin, which supports the prominent surface ruffles and microvilli best seen by scanning electron microscopy (Fig. 29.2).

Recent studies have identified a number of molecules which, by interacting with F-actin, may be involved in the generation of the hairy appearance of the malignant cells. These include pp52 (LSP-1), Gas-7, and EPB4.1L2—recently found by gene microarray analysis to be overexpressed in HCs (Table 29.3).4 pp52 has been previously found to be abundant in the F-actin-rich protrusions of HCs,37 while, by interacting

Figure 29.1 The ultrastructure of the ribosome-lamellar complex. In the lower right part of this electron micrograph, the R-L complex is sectioned longitudinally, while on the left the complex is cut obliquely. The inset shows the complex in transverse section. In three dimensions, the R-L complex probably resembles a coiled roll of chicken wire

Figure 29.1 The ultrastructure of the ribosome-lamellar complex. In the lower right part of this electron micrograph, the R-L complex is sectioned longitudinally, while on the left the complex is cut obliquely. The inset shows the complex in transverse section. In three dimensions, the R-L complex probably resembles a coiled roll of chicken wire

Figure 29.2 The surface structure of HCs. This scanning electron micrograph shows the surface of two adjacent HCs. Note the distinctive mixture of surface ruffles and microvilli

with F-actin, ectopically expressed Gas 7 induces excessive surface projections and dramatic changes in cell shape.38 EPB4.1L2 is also involved in the regulation of cell shape through interaction with p-actin underneath the plasma membrane.4

In addition to possessing a unique morphology, HCs are unusual among lymphoid cells in displaying a spectrum of features normally associated with monocytes and macrophages. HCs are able to phagocytose a range of particles and microorganisms,39 a property that has recently been linked to the specific upregulation of annexin A1, CD68, and a novel serine carboxypeptidase CPVL which was first identified in macrophages.40 Although the expression of CD11c is possibly an activation feature of HCs and is also found on certain other lymphoid cell types, this integrin a chain, together with CD63, is commonly regarded as a macrophage marker. In addition, HCs have been shown to overexpress c-Maf, a transcription factor linked to macrophage differentiation.41 Finally, overexpression or underexpression by HCs of a number of genes outlined in Table 29.3 could be relevant for the unusual tissue distribution of HCs and for the matrix remodeling by the malignant cells that are such distinctive features of HCL.

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