Hairy Cell Leukemia

Formerly called leukemic reticuloendotheliosis,210-215 hairy cell leukemia is a well-characterized clinico-pathologic entity for which several successful treatment strategies exist. This disorder was first recognized by Rosenthal and colleagues212 as well as Bouroncle and co-workers210 in the 1950s, but was first characterized as hairy cell leukemia after Schrek and Donnelly213 described the hairy villous cytoplasmic projections of the leukemic cells viewed under phase microscopy in 1966.

Hairy cell leukemia is characterized by chronic anemia or pancytopenia, with variable numbers of hairy cells in the peripheral blood, progressive splenomegaly, slight hepatomegaly, and minimal or no lymphadenopathy.214 Hairy cells are clonal late B cells, displaying certain immunological features of activation (strong expression of surface immunoglobulin, light chain restricted, CD22, CD25, CD7 and CD40 ligand, CD110).215 Unusual infections, such as atypical mycobacterial dissemination, may occur.216 The differential diagnosis of this condition includes malignant lymphoma, CLL, myelofibrosis, acute monocytic leukemia, or idiopathic hypersplenism. Wright-stained hairy cells have an agranular clay-blue cytoplasm and are slightly larger than mature lymphocytes. The cell border is irregular and serrated due to characteristic "hair" cytoplasmic projections or filamentous villi. In some cells, only scant or disrupted cytoplasm is present (Plate 3-2J). The nucleus may be eccentric and is usually round but may be oval or indented with a distinct nuclear membrane. The chromatin is delicate and lacy, rather than clumped as in mature lymphocytes. Single

Figure 3—1. Ultrastructural features of a hairy cell within splenic sinusoid. Note typical multiple filamentous cytoplasmic projections. Characteristic ribosome-lamella complexes are not readily seen at this magnification (x 9000).

nucleoli are occasionally evident. An uncommon prolymphocyte variant is characterized by large hairy cells (12 to 30 mm) containing round central nuclei, with condensed chromatin and a single prominent small- to medium-sized nucleolus in approximately 90 percent of cells.217 The morphology of hairy cells may also be readily visualized by the use of supravital stains or phase microscopy. The most characteristic ultrastructural findings are pseudopods and long cytoplasmic microvilli on the cell surface that measure less than 4 |im in length218 (Figure 3-1). In addition to several cellular organelles, a distinctive ribosomal-lamellar complex may be noted.219

A positive tartrate-resistant acid phosphatase (TRAP) reaction probably also reflective of B-cell activation, historically was a useful confirmatory cytochemical test for the diagnosis of hairy cell leukemia.220 While hairy cells in the vast majority of cases show a positive TRAP stain (Plate 3-2K), the proportion of positive cells is variable and, in rare patients, may be nega-tive.220>221 Patients with lymphocytic lymphoma, T-cell CLL, PLL, and Sezary syndrome may also be TRAP positive.221-223 Because of these limitations, the diagnosis of hairy cell leukemia now rests in the characteristic morphology on trephine biology, typical immunophenotypic pattern (B cells that are CD22+, CD25+, and CD11c+), and characteristic immunocytochemical stains (e.g., DBA44).224 High levels of cyclin D1 expression, noted in patients with mantle cell lymphoma [with a t(11;14)(q13;q32)] cytogenetic translocation have also been noted in marrows from hairy cell leukemia patients.225

The expression of B-cell activation antigens on the surface of hairy cells has taken on a new importance given the availability of monoclonal antibodies with therapeutic utility. An anti-CD25 monoclonal antibody fused to a truncated form of pseudomonas exotoxin may have such a role.226 Recently a report described responses in a hairy cell leukemia patient failing nucleoside analogue therapy treated with a toxin-linked anti-CD22 antibody.227

Attempts at bone marrow aspiration are usually unsuccessful because of marked increase in the reticulum fibers. Diagnostic bone marrow biopsies from patients with hairy cell leukemia reveal diffuse bone marrow involvement (although patchy distribution is also rarely possible) and a hypercellular marrow often diffusely infiltrated with hairy cells (Plate 3-2L,M). It is presumed that hairy cells either directly or indirectly suppress normal hematopoiesis.228 The mechanism of fibrosis in hairy cell leukemia is likely a reaction to certain surface characteristics and secreted products (e.g., fibronectin) of the malignant cell.214 Cells derived from patients with hairy cell leukemia were shown to produce basic fibroblast growth fac-tor,229 which could be a survival and pro-fibrotic factor.

Marked splenomegaly eventually develops in most patients, with 50 percent weighing greater than 1 kg. The cut surface of the spleen is firm, red, and may display old infarctions. The splenic white pulp is conspicuous and gross tumor nodules are not present. Hairy cells infiltrate the red pulp, with the extensive involvement resulting in marked widening of the pulp cords. A reactive proliferation of ellipsoidal histiocytes also occurs in the red pulp, and reticulum fibers are increased. Such phagocytic cells are partly responsible for the secondary hypersplenism that occurs due to extension of the red pulp.230 The red pulp encroaches on the white pulp, usually resulting in reduction in the diameter of the Malpighian corpuscles, which eventually consist of small lymphocytes, devoid of reaction centers. Formation of characteristic sinuslike structures (or blood lakes) with hairy cells arranged in a luminal side has been described. Those blood lakes may be seen grossly (Plate 3-2N,O). The white pulp eventually atrophies. Morphologically, hairy cells appear to have indistinct nucleoli and no mitosis. Ultrastructural studies suggest that hairy cells adhere to many cell surfaces and structures within the spleen.230,231 Collections of hairy cells within the subendothelial lymphatic sinuses and cords may impede splenic blood flow, resulting in sinus dilation with formation of abnormal sinuses and blood-filled spaces.201,231

Involvement of the liver by hairy cell leukemia is not usually a clinical problem (Plate 3-2P), although sensitive techniques may identify hairy cells in liver biopsy specimens.232 Abnormal liver function tests are more likely to be associated with other diseases rather than direct hairy cell infiltration of the liver.232

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