Fludarabine

Hairy cell leukemia variant (HCL-V) is a rare lymphoproliferative disorder. We report a case of HCL-V with an intrasinusoidal pattern of bone marrow involvement without interstitial or diffuse infiltration that is typical of HCL and its variant. The peripheral blood and bone marrow aspirates demonstrated abnormal lymphoid cells with cytoplasmic projections that were weakly positive for tartrate-resistant acid phosphatase cytochemical staining. Immunostaining of the bone marrow biopsy specimen showed that these cells were strongly positive for CD20, located within bone marrow sinusoids, and weakly positive for DBA44. By flow cytometry, these cells were positive for CD19, CD20, CD11c, and CD103, exhibited λ light chain restriction, and were negative for CD25. The patient was initially diagnosed as having splenic lymphoma with villous lymphocytes (SLVL) or splenic marginal zone lymphoma (SMZL) (World Health Organization designation) and treated with fludarabine followed by splenectomy with simultaneous liver biopsy. The pathologic analysis of the spleen revealed infiltration of red pulp by the critical cells without white pulp involvement, which is characteristic of HCL and HCL-V but not of SLVL (SMZL). This case illustrates an atypical marrow presentation of HCL-V and emphasizes the need to correlate all clinical and pathologic data, including tissue biopsy, in reaching a diagnosis.

(Arch Pathol Lab Med. 2005;129:395-398)

Hairy cell leukemia (HCL) was first described in 1958 by Bouroncle et al' and was called lenkemic reticuloendothcliosis. Classic HCL (HCL-C) comprises 2% of lymphoid leukemias, with a median patient age at onset of 55 years. The male-female ratio is 5:1.1,2 It has been frequently characterized by pancytopenia, monocytopenia, splenomegaly, absence of peripheral lymphadenopathy, and marrow fibrosis, which typically contribute to an unsuccessful bone marrow aspiration. A bone marrow core biopsy specimen contains patchy interstitial infiltrates of enlarged lymphoid cells with a low nuclear-cytoplasmic ratio, reticular chromatin, and cytoplasmic projections.

A variant form of HCL (HCL-V) was recognized by Cawley et aP in 1980. It is an uncommon disorder that accounts for approximately 0.4% of chronic lymphoid malignancies and represents 10% of all HCL cases.4 The variant form of HCL is a distinct clinicopathologic entity with intermediate features between HCL-C and B-cell prolymphocytic leukemia,5,6 with a median patient age of onset of 71 years. Frequently, HCL-V is characterized by splenomegaly and a high white blood cell count without neutropenia or monocytopenia and has hypercellular marrow that can be aspirated.7

Splenic lymphoma with circulating villous lymphocytes (SLVL) was first described by MeIo et al8 in 1987 and was defined as the leukemic form of splenic marginal zone lymphoma (SMZL), with a median patient age of onset of 69 years.9 Splenic marginal zone lymphoma seems to affect both sexes equally."1 The patients usually have leukocytosis and splenomegaly with successful bone marrow aspiration.h In addition, HCL-C, HCL-V, and SMZL have some common features, including splenomegaly, peripheral blood and bone marrow infiltration by villous lymphoid cells, and B-lymphocyte immunophenotype.6 Also, SMZL has characteristic intrasinusoidal bone marrow involvement that is considered a prominent and fairly reliable pattern of bone marrow involvement." n However, this type of marrow involvement is not specific and is also found in HCL-C but usually seen in association with other types of bone marrow involvement, such as interstitial, diffuse, or nodular patterns.12,13 We herein report a case of HCL-V with an exclusive intrasinusoidal pattern of bone marrow involvement. To our knowledge, the solely intrasinusoidal infiltrates of the marrow have not been described for HCL-V, which can be confused with SMZL.

REPORT OF A case

A 68-year-old woman presented with significant splenomegaly (5 cm below the left costal margin, 23 cm on ultrasound) and hepatomegaly. There was no lymphadenopathy on physical examination or abdominal ultrasound. She had night sweats but no fever. At presentation, the hemoglobin level was 12.5 g/dL, white blood cell count was 35800/µL (neutrophils, 9%; lymphocytes, 88%; monocytes, 1%; and eosinophils, 2%), and platelet count was 146 × 10^sup 3^/µL. Bone marrow aspiration and biopsy were performed, and the findings were interpreted as consistent with SLVL based on the characteristics of the blood and bone marrow lymphocytes, the pattern of the lymphoid infiltration, immunohistochemical stains, and flow cytometry profiles. She had no response to chlorambucil and only a transient response to fludarabine chemotherapy, with recurrence in her blood 4 months after treatment; therefore, she subsequently underwent splenectomy.

PATHOLOGIC FINDINGS

Blood smear at the time of diagnosis revealed lymphocytosis, which was composed of 75% of the white blood cells. They were medium in size with a moderate amount of cytoplasm, some with nucleoli, and a few with cytoplasmic projections. Bone marrow aspiration showed 28% of lymphoid cells, similar to the blood smear, with a reticular chromatin pattern, cytoplasmic projections, and indistinct nucleoli (Figure 1, A). Tartrate-resistant acid phosphatase (TRAP) cytochemical stain was weakly positive in the marrow cells but negative in those of the peripheral blood. The bone marrow biopsy specimen showed normal cellularity for the patient's age. The architectural features were intact with no evidence of paratrabecular aggregates of lymphoid cells. The section showed a distinct intrasinusoidal population of CD20^sup +^ lymphocytes (Figure 1, B). The lymphocytes had abundant cytoplasm and indistinct nucleoli. Mitotic activity was normal. DBA44 was weakly positive in atypical lymphoid cells. The remainder of the marrow showed a good hematopoietic reserve and slightly increased reticulin.

Flow cytometry showed a population of cells with slightly greater forward and side scatter than that of normal lymphocytes. These atypical cells expressed B-cell markers with λ light chain restriction, which were positive for CD19, CD20, CD23, FMC7, CDlIc, and CD103 but negative for CD25 (Figure 2, A and B), CD5, and CDlO.

The spleen biopsy specimen demonstrated diffuse infiltration of red pulp cords and sinusoids by leukemic lymphoid cells whose morphologic features closely resembled those of small lymphocytes with moderate cytoplasm. A few residual atrophie germinal centers of the white pulp were seen. The reticulin stain did not show any residual nodular pattern. The liver biopsy specimen showed portal triads and sinusoids infiltrated with lymphoid cells. Immunostains revealed that these cells were positive for CD20 and CD79a, weakly positive for DBA44, and negative for CD25.

COMMENT

Intrasinusoidal B-cell infiltration has been considered a prominent and reliable pattern of marrow involvement of SMZL (SLVL).14 This pattern can sometimes be masked by a diffuse interstitial lymphomatous infiltration in routine stains" but can be distinguished by immunohistochemical study with anti-CD20, which highlights the villous lymphocytes within the marrow sinusoids.12,13 Kent et al13 found that the intrasinusoidal infiltration by anti-CD20 in 10 (83%) of 12 patients with SMZL (SLVL) was always seen in association with other patterns of the bone marrow involvement; the intrasinusoidal infiltration was also observed in 8 (73%) of 11 patients with HCL-C but was subtle compared with a more extensive interstitial infiltration.13 Hounieu et al14 studied 209 bone marrow biopsy specimens from patients with HCL-C by immunohistochemical analysis for DBA44 and found that only one case had exclusively intravascular involvement without using the term intrasinusoidal as described and well recognized later in SMZL by Franco et al11 in 1996 and Labouyire et al12 in 1997. However, DBA44 antibody, which facilitates the detection of HCL within bone marrow, is not specific for HCL; it has been found to be immunoreactive with 71% of SMZL (SLVL).12 Matutes et al4 described bone marrow histologie features in 29 cases with HCL-V in which most cases (79%) had interstitial infiltration with scattered hairy cells lying within the sinusoids and 21% had a mixed pattern (nodular and interstitial). However, none of their HCL-V cases had exclusive intrasinusoidal infiltration as seen in our case.

The circulating cells of HCL-V have morphologic features similar to prolymphocytes and HCL-C. They contain abundant villous cytoplasm and a round, occasionally bilobed nucleus, usually with a prominent nucleolus.5 The SMZL cells, which are smaller than HCL-V cells, have more condensed chromatin, and the cytoplasm is villous, usually moderate in amount, but can be scant and more basophilic.4,15 The cytoplasmic projections are thin, short, and uneven or sometimes polar in distribution. Half of the SMZL cases have a small but distinct nucleolus.15 The morphologic findings of HCL-V and SMZL can be similar, as observed in our case in that the atypical lymphoid cells resemble either SMZL or HCL-V, which raises a challenge in the morphologic diagnosis.

Flow cytometric immunophenotyping is helpful in the differential diagnosis of HCL-C, HCL-V, and SMZL. All entities resemble mature B cells and consistently express CD19, CD20, CD22, and FMC7 but not CD5.h Typically, HCL-C is negative for CDlO and CD23, positive for CD25, and brightly positive for CDlIc and CD103; the κ light chain restriction occurs as often as λ. Typically, HCL-V is negative for CDlO, CD23, CD25, and dim CDlIc and variably expresses CDl 03; the κ restriction is less often than λ. Usually, SMZL is negative for CD103 and variably expresses CD25, CD23, CDlO, and CDlIc; it exhibits κ restriction more often than λ.6,16 In our case, CDlOS^sup +^, CD25^sup -^ B-cell immunophenotypical features favor the diagnosis of HCL-V.

Tartrate-resistant acid phospatase positivity has been reported in some SMZL patients and up to 60% of cases of HCL-V.5 TRAP is often hampered by the scarcity of the neoplastic cells in blood and bone marrow aspirate specimens. As the availability of immunophenotypic procedures has increased, TRAP studies are less frequently used to confirm the diagnosis. Moreover, TRAP has been occasionally found in other low-grade lymphoproliferative disorders. Therefore, it has limited value in differentiating among B-cell lymphoproliferative disorders.

Spleen pathologic findings seem to be the most reliable method of distinguishing HCL-V from SMZL. Typically, the spleen in HCL-V shows expansion of the red pulp with no residual or atrophie white pulp, as found in HCL-C; lymphoid cells are lying in the sinusoids, whereas SMZL preferentially infiltrates splenic white pulp.4 It is clear that the spleen pathologic findings in our case are compatible with HCL, and when incorporated with flow cytometry analysis, the diagnosis of HCL-V is established. The clinical, blood, and bone marrow morphologic features and immunophenotypic profiles are given in the Table.

The variant form of HCL is a distinct clinicopathologic entity that seems to be resistant to various therapeutic modalities.17 The clinical course of HCL-V is more aggressive with shorter survival than HCL-C.1S In contrast to HCL-C or SLVL, HCL-V patients did not respond to splenectomy or interferon alfa.5-7 There are limited reports of HCL-V patients treated with 2-chlorodeoxyadenosine, most of whom have poorer clinical outcome and a lower response rate than those patients with HCL-C.17,19

In conclusion, we present a unique case of HCL-V that shows bone marrow involvement by clonal B cells with a solely intrasinusoidal pattern. This case demonstrates the heterogeneity of HCL-V and the importance of incorporating morphologic features, immunophenotype, and other tissue pathologic findings to reach an appropriate diagnosis.

References

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12. Labouyrie E, Marit G, Vial JP, et al. lntrasinusoidal bone marrow involvement by splenic lymphoma with villous lymphocytes: a helpful immunohistologic feature. Mod Pathol. 1997;10:1015-1020.

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14. Hounieu H, Chittal SM, Al Saati T, et al. Hairy cell leukemia: diagnosis of bone marrow involvement in paraffin-embedded sections with monoclonal antibody DBA44. Am J Clin Pathol. 1992:98:26-33.

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16. Melo JV, Hedge U, Parreira A, et al. Splenic B cell lymphoma with circulating lymphocytes: differential diagnosis of B cell leukemia with large spleens. J Clin Pathol. 1987:40:642-651.

17. Blasinska-Morawiec M, Robak T, Krykowski E, Hellmann A, Urbanska-Rys H. Hairy cell leukemia variant treated with 2-chlorodeoxyadenosine-a report of 3 cases. Leuk Lymphoma. 1997;25:382-385.

18. Tetreault SA, Robbins BA, Saven A. Treatment of Hairy cell leukemia-variant with cladribine. Leuk Lymphoma. 1999:35:347-354.

19. Robak T, Blasinska-Morawiec M, Blonski ), et al. 2-chlorodeoxydenosine (cladribine) in the treatment of hairy ceil leukemia and hairy cell leukemia variant: 7 year experience in Poland. Eur J Haematol. 1999:62:49-56.

Charin Ya-In, MD; Joseph Brandwein, MD; Dominic Pantalony, MD; Hong Chang, PhD, MD, FRCPC

Accepted for publication October 6, 2004.

From the Departments of Laboratory Hematology (Drs Ya-In, Pantalony, and Chang) and Medical Oncology and Hematology (Dr Brandwein), Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, Ontario.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Hong Chang, PhD, MD, FRCPC, Department of Laboratory Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, 4-320, Toronto, Ontario, Canada M5C 2M9 (e-mail: hong.chang@uhn.on.ca ).

Copyright College of American Pathologists Mar 2005
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